Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds

ABSTRACT

Disclosed are compounds which inhibit beta-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer&#39;s disease. Also disclosed are pharmaceutical compositions that include a compound which inhibits beta-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer&#39;s disease both prophylactically and therapeutically with such pharmaceutical compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional application No.60/160,067, which was converted pursuant to 37 C.F.R. § 1.53(b) fromU.S. Ser. No. 09/102,507, filed Jun. 22, 1998; the disclosure of whichis incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds which inhibit β-amyloid peptiderelease and/or its synthesis, and, accordingly, have utility in treatingAlzheimer's disease.

2. References

The following publications, patents and patent applications are cited inthis application as superscript numbers:

1 Glenner, et al., Biochem. Biophys. Res. Commun., 120: 885-890 (1984) 2U.S. Pat. No. 4,666,829 3 Selkoe, Neuron, 6: 487-498 (1991) 4 Goate, etal., Nature, 349: 704-706 (1990) 5 Chartier Harlan, et al., Nature, 353:844-846 (1989) 6 Murrell, et al., Science 254: 97-99 (1991) 7 Mullan, etal., Nature Genet., 1: 345-347 (1992) 8 Schenk, et al., InternationalPatent Application Publication No. WO 94/10569, “Methods andCompositions for the Detection of Soluble B-Amyloid Peptide”, published11 May 1994 9 Selkoe, Scientific American, “Amyloid Protein andAlzheimer's Disease”, pp. 2-8, November, 1991 10 Tetrahedron Letters,34(48), 7685 (1993) 11 Losse, et al., Tetrahedron, 27: 1423-1434 (1971)12 Citron, et al., Nature, 360: 672-674 (1992) 13 Hansen, et al., J.Immun. Meth., 119: 203-210 (1989) 14 U.S. Pat. No. 3,598,859 15Ogliaruso and Wolfe, Synthesis of Lactones and Lactams, Patai, et al.Editor, J. Wiley & Sons, New York, New York, U.S.A., pp. 1085 et seq.(1993). 16 Ugi, et al., Tetrahedron, 52(35): 11657-11664 (1996) 17Blade-Font, Tetrahedron Lett., 21: 2443 (1980). 18 Freidinger, et al.,J. Org. Chem., 47: 104-109 (1982) 19 Semple, et al., J. Med. Chem., 39:4531-4536 (1996). 20 Holladay, et al., J. Org. Chem., 56: 3900-3905(1991). 21 Donaruma, et al., Organic Reactions, 11: 1-156 (1960) 22Wolff, Organic Reactions 3: 307-336 (1946) 23 Krow, et al., J. Org.Chem., 61: 5574-5580 (1996) 24 Tetrahedron, 35: 2433 (1979) 25 Gracias,et al., J. Am. Chem. Soc., 117: 8047-8048 (1995) 26 Milligan, et al., J.Am. Chem. Soc., 117: 10449-10459 (1995) 27 Miller, et al., J. Am. Chem.Soc., 118: 9606-9614 (1996) 28 March, Advanced Organic Chemistry,Reaction Mechanisms and Structure, 2nd Edition, McGraw-Hill BookCompany, New York, New York, U.S.A. (1977) 29 Colombo, et al.,Tetrahedron Lett., 35(23): 4031-4034 (1994) 30 Rogriguez, et al.,Tetrahedron, 52: 7727-1736 (1996) 31 Parsons, et al., Biochem. Biophys.Res. Comm., 117: 108-113 (1983) 32 Watthey, et al., J. Med. Chem., 28:1511-1516 (1985) 33 Armstrong, et al., Tetrahedron Lett., 35: 3239(1994) 34 King, et al., J. Org. Chem., 58: 3384 (1993). 35 Hu, et al.,Tetrahedron Lett., 36(21): 3659-3662 (1995). 36 Wada, et al., Bull.Chem. Soc. Japan, 46: 2833-2835 (1973) 37 Gaetzi, Chem. Abs., 66: 28690m38 Wheeler, et al., Organic Syntheses, Coll. Vol. VI, p. 840 39 J. Med.Chem., 28(12): 1886 (1985) 40 Brenner, et al., U.S. Pat. No. 2,938,02941 Evans, et al., J. Am. Chem. Soc., 112: 4011-4030 (1990) 42 Micouin,et al., Tetrahedron, 52: 7719-7726 (1996) 43 Butcher, et al.,Tetrahedron Lett., 37(37): 6685-6688 (1996) 44 M.L. Reupple, et al., J.Am. Chem. Soc., 93: 7021 et seq. (1971) 45 P.A.S. Smith, OrganicReactions, 3: 337-449 (1946) 46 K. Orito, et al., Tetrahedron, 36:1017-1021 (1980) 47 Krimm, Chem. Ber., 91: 1057 (1958) 48 Suda, et al.,J. Chem. Soc. Chem Comm., 949-950, (1994) 49 Barton, et al., J. Chem.Soc., 1764-1767 (1975) 50 Kitagawa, et al., J. Am. Chem. Soc., 117:5169-5178 (1975) 51 Akhatar, et al., J. Org. Chem. 55: 5222-5225 (1990)52 Nedenskov, et al., Acta Chem. Scand., 12: 1405-1410 (1958) 53Sakakida, et al., Bull. Chem. Soc. Japan, 44: 478-480 (1971) 54 Hoffman,et al., Tet. Lett., 30: 4207-4210 (1989) 55 Vedejs, et al., Tet. Lett.,33: 3261-3264 (1992) 56 van der Steen, et al., Tetrahedron, 47,7503-7524 (1991) 57 Hart, et al., Chem Rev., 89: 1447-1465 (1989) 58Lowe, et al., Bioorg. Med. Chem. Lett., 4: 2877-2882 (1994) 59 McKennis,Jr., et al., J. Org. Chem., 28: 383-387 (1963) 60 Shirota, et al., J.Med. Chem., 20: 1623-1627 (1977) 61 Overberger, et al., J. Am. Chem.Soc., 85: 3431 (1963) 62 Herschmann, Helv. Chim. Acta, 32: 2537 (1949)63 Overberger, et al., Macromolecules, 1: 1 (1968) 64 Busacca, et al.,Tet. Lett., 33: 165-168 (1992) 65 Croisier, et al., U.S. Pat. No.4,080,449 66 J.A. Robl, et al., Tetrahedron Lett., 36(10): 1593-1596(1995) 67 Flynn, et al., J. Med. Chem., 36: 2420-2423 (1993) 68 Orito,et al., Tetrahedron, 36: 1017-1021 (1980) 69 Kawase, et al., J. Org.Chem., 54: 3394-3403 (1989) 70 Lowe, et al., J. Med. Chem., 37:3789-3811 (1994) 71 Robl, et al., Bioorg. Med. Chem. Lett., 4: 1789-1794(1994) 72 Skiles, et al., Bioorg. Med. Chem Lett., 3: 773-778 (1993) 73Grunewald, et al., J. Med. Chem., 39(18): 3539 (1996) 74 Thomas, et al.,J. Chem. Soc., Perkin II, 747 (1986) 75 Warshawsky, et al., Bioorg. Med.Chem. Lett., 6: 957-962 (1996) 76 Ben-Ishai, et al., Tetrahedron, 43:439-450 (1987) 77 van Niel et al., Bioorg. Med. Chem. Lett., 5:1421-1426 (1995) 78 Kawase, et al., J. Org. Chem., 54: 3394-3403 (1989)79 Edwards, et al., Can. J. Chem., 49: 1648-1658 (1971) 80 Milligan, etal., J. Am. Chem. Soc., 117: 10449-10459 (1995) 81 Curran et al., Tet.Lett., 36: 191-194 (1995) 82 Slusarchyk, et al., Bioorg. Med. Chem.Lett., 5: 753-758 (1995) 83 Wyvratt, et al., Eur. Pat. Appl. 61187(1982) 84 Cornille, et al., J. Am. Chem. Soc., 117: 909-917 (1995) 85Kolc, Coll. Czech. Chem. Comm., 34: 630 (1969) 86 Dickerman, et al., J.Org. Chem., 14: 530 (1949) 87 Dickerman, et al., J. Org. Chem., 20: 206(1955) 88 Dickerman, et al., J. Org. Chem., 19: 1855 (1954) 89 Hoffman,et al., J. Org. Chem., 27: 3565 (1962) 90 Wasserman, et al., J. Am.Chem. Soc., 103: 461-2 (1981) 91 Crombie, et al., Tetrahedron Lett.,27(42): 5151-5154 (1986) 92 Yokoo, et al., Bull, Chem. Soc. Jap., 29:631 (1956) 93 Burkholder, et al., Biog. Med. Chem. Lett., 2: 231 (1993)94 Karanewsky, U.S. Pat. No. 4,460,579 95 Kametani, et al.,Heterocycles, 9: 831-840 (1978) 96 Yanganasawa, et al., J. Med. Chem.,30: 1984-1991 (1987) 97 J. Das et al., Biorg. Med. Chem. Lett., 4:2193-2198 (1994)

All of the above publications, patents and patent applications areherein incorporated by reference in their entirety to the same extent asif each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety.

3. State of the Art

Alzheimer's Disease (AD) is a degenerative brain disorder characterizedclinically by progressive loss of memory, cognition, reasoning, judgmentand emotional stability that gradually leads to profound mentaldeterioration and ultimately death. AD is a very common cause ofprogressive mental failure (dementia) in aged humans and is believed torepresent the fourth most common medical cause of death in the UnitedStates. AD has been observed in races and ethnic groups worldwide andpresents a major present and future public health problem. The diseaseis currently estimated to affect about two to three million individualsin the United States alone. AD is at present incurable. No treatmentthat effectively prevents AD or reverses its symptoms and course iscurrently known.

The brains of individuals with AD exhibit characteristic lesions termedsenile (or amyloid) plaques, amyloid angiopathy (amyloid deposits inblood vessels) and neurofibrillary tangles. Large numbers of theselesions, particularly amyloid plaques and neurofibrillary tangles, aregenerally found in several areas of the human brain important for memoryand cognitive function in patients with AD. Smaller numbers of theselesions in a more restrictive anatomical distribution are also found inthe brains of most aged humans who do not have clinical AD. Amyloidplaques and amyloid angiopathy also characterize the brains ofindividuals with Trisomy 21 (Down's Syndrome) and Hereditary CerebralHemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, adefinitive diagnosis of AD usually requires observing the aforementionedlesions in the brain tissue of patients who have died with the diseaseor, rarely, in small biopsied samples of brain tissue taken during aninvasive neurosurgical procedure.

The principal chemical constituent of the amyloid plaques and vascularamyloid deposits (amyloid angiopathy) characteristic of AD and the otherdisorders mentioned above is an approximately 4.2 kilodalton (kD)protein of about 39-43 amino acids designated the β-amyloid peptide (AP)or sometimes A, AP or /A4. B-Amyloid peptide was first purified and apartial amino acid sequence was provided by Glenner, et al.¹ Theisolation procedure and the sequence data for the first 28 amino acidsare described in U.S. Pat. No. 4,666,829².

Molecular biological and protein chemical analyses have shown that theβ-amyloid peptide is a small fragment of a much larger precursor proteintermed the amyloid precursor protein (APP), that is normally produced bycells in many tissues of various animals, including humans. Knowledge ofthe structure of the gene encoding APP has demonstrated that β-amyloidpeptide arises as a peptide fragment that is cleaved from APP byprotease enzyme(s). The precise biochemical mechanism by which theβ-amyloid peptide fragment is cleaved from APP and subsequentlydeposited as amyloid plaques in the cerebral tissue and in the walls ofthe cerebral and meningeal blood vessels is currently unknown.

Several lines of evidence indicate that progressive cerebral depositionof β-amyloid peptide plays a seminal role in the pathogenesis of AD andcan precede cognitive symptoms by years or decades. See, for example,Selkoe³. The most important line of evidence is the discovery thatmissense DNA mutations at amino acid 717 of the 770-amino acid isoformof APP can be found in affected members but not unaffected members ofseveral families with a genetically determined (familial) form of AD(Goate, et al.⁴; Chartier Harlan, et al.⁵; and Murrell, et al.⁶) and isreferred to as the Swedish variant. A double mutation changinglysine⁵⁹⁵-methionine⁵⁹⁶ to asparagine⁵⁹⁵-leucine⁵⁹⁶ (with reference tothe 695 isoform) found in a Swedish family was reported in 1992 (Mullan,et al.⁷). Genetic linkage analyses have demonstrated that thesemutations, as well as certain other mutations in the APP gene, are thespecific molecular cause of AD in the affected members of such families.In addition, a mutation at amino acid 693 of the 770-amino acid isoformof APP has been identified as the cause of the β-amyloid peptidedeposition disease, HCHWA-D, and a change from alanine to glycine atamino acid 692 appears to cause a phenotype that resembles AD is somepatients but HCHWA-D in others. The discovery of these and othermutations in APP in genetically based cases of AD prove that alterationof APP and subsequent deposition of its β-amyloid peptide fragment cancause AD.

Despite the progress which has been made in understanding the underlyingmechanisms of AD and other β-amyloid peptide related diseases, thereremains a need to develop methods and compositions for treatment of thedisease(s). Ideally, the treatment methods would advantageously be basedon drugs that are capable of inhibiting β-amyloid peptide release and/orits synthesis in vivo.

SUMMARY OF THE INVENTION

This invention is directed to the discovery of a class of compoundswhich inhibit β-amyloid peptide release and/or its synthesis and,therefore, are useful in the prevention of AD in patients susceptible toAD and/or in the treatment of patients with AD in order to inhibitfurther deterioration in their condition. The class of compounds havingthe described properties are defined by Formulas I-VI below:

wherein R¹ is selected from the group consisting of aryl, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkenyl, substituted alkynyl, substituted cycloalkyl,substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;

R′ is selected from the group consisting of aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heterocyclic, heteroaryl, heterocyclooxy, —CH₃, —CH═CH₂, —CH═CHR¹,—CH═CR¹R¹, —CR¹═CH₂, —CR¹═CHR¹, —CR¹═CR¹R¹, —C═CH and —C═CR¹; with theproviso that when R′ is heteroaryl or heterocyclic, there is no N in R′at a position beta to the C═Q group;

Q is S or O;

R¹⁵ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, heterocyclic and heteroaryl;

R^(15′) is selected from the group consisting of hydrogen, hydroxyl,alkyl, substituted alkyl, aryl, heterocyclic and heteroaryl;

W, together with —C(H)_(p)C(═X)—, forms a cycloalkyl, cycloalkenyl,heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl groupwherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substitutedcycloalkyl or substituted cycloalkenyl group is optionally fused to forma bi- or multi-fused ring system (preferably no more than 5 fused rings)with one or more ring structures selected from the group consisting ofcycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which,in turn, each of such ring structures are optionally substituted with 1to 4 substituents selected from the group consisting of hydroxyl, keto,thioketo, halo, alkoxy, substituted alkoxy, thioalkoxy, substitutedthioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, substituted amino, —NHC(O)R⁴, —NHSO₂R⁴, —C(O)NH₂, —C(O)NHR⁴,—C(O)NR⁴R⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NHR and —S(O)₂NR⁴R⁴, where each R⁴is independently selected from the group consisting of alkyl,substituted alkyl, aryl and heteroaryl;

X is selected from the group consisting of oxo (═O), thiooxo (═S),hydroxyl (—H,—OH), thiol (H,—SH) and hydro (H,H);

Y is represented by the formula:

wherein each R² is independently selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;

Z is represented by the formula —T—C(X′)(X″)C(O)— where T is selectedfrom the group consisting of a bond covalently linking R¹ to—C(X′)(X″)—, oxygen, sulfur, and —NR⁵ where R⁵ is hydrogen, acyl, alkyl,substituted alkyl, aryl, heterocyclic or heteroaryl group;

R^(5′) is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic orheteroaryl group;

X′ and X″ are independently selected from the group consisting ofhydrogen, fluoro, alkyl, substituted alkyl; aryl, heteroaryl,heterocyclic, —OR⁵′, —SR⁵, —N(R⁵)₂, —N(CO)OR¹⁵ and —N₃, with the provisothat at least one of X′ or X″ is other than hydrogen, hydroxy or fluoro,and with the further proviso that both X′ and X″ cannot both be—OR^(5′), —SR⁵, —N(R⁵)₂, —N(CO)OR¹⁵ and —N₃; further, neither X′ and X″can be —OR⁵′, —SR⁵, —N(R⁵)₂, —N(CO)OR¹⁵ or —N₃ when T is other than abond covalently linking R¹ to —C(X′)(X″)—;

n is an integer equal to 1 or 2;

p is an integer equal to 0 or 1 such that when p is zero, the ringdefined by W and —C(H)_(p)C(═X)— is unsaturated at the carbon atom ofring attachment to Y and when p is one, the ring is saturated at thecarbon atom of ring attachment to Y,

with the following provisos:

when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, thenW, together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15is hydrogen, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is α-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen,then W, together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is α-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen,then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is α-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen,then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 ishydrogen, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, thenW, together with >CH and >C═X, does not form a2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15is hydrogen, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1—N(R¹⁵) is (2,5-dimethoxyphenyl)ureylenyl and R2 is methyl, thenW, together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is hydrogen,then W, together with >CH and >C═X, does not form a7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

Accordingly, in one of its method aspects, this invention is directed toa method for inhibiting β-amyloid peptide release and/or its synthesisin a cell which method comprises administering to such a cell an amountof a compound or a mixture of compounds as described herein effective ininhibiting the cellular release and/or synthesis of β-amyloid peptide.

Because the in vivo generation of β-amyloid peptide is associated withthe pathogenesis of AD^(8,9), the compounds described herein can also beemployed in conjunction with a pharmaceutical composition toprophylactically and/or therapeutically prevent and/or treat AD.Accordingly, in another of its method aspects, this invention isdirected to a prophylactic method for preventing the onset of AD in apatient at risk for developing AD by administering to the patient apharmaceutical composition comprising a pharmaceutically inert carrierand an effective amount of one or more of the compounds describedherein.

In yet another of its method aspects, this invention is directed to atherapeutic method for treating a patient with AD in order to inhibitfurther deterioration in the condition of that patient which methodcomprises administering to said patient a pharmaceutical compositioncomprising a pharmaceutically inert carrier and an effective amount of acompound or a mixture of compounds as described herein.

Preferred R′ groups include, by way of example, all of the aryl(including substituted aryl), cycloalkyl, and substituted cycloalkylgroups defined for R′ above as well as the following additional groups:

thiophene-2-yl, 2-furanyl, cyclopropyl, cyclobutyl, 1-phenylcyclopropyl,cyclopentyl, cyclohexyl, cycloheptyl, 2-benzofuranyl,5-chloro-benzofuran-2-yl, 5,5-dimethyl-butyrolactone-4-yl,4-methylsulfonyl-phenyl, cis-2-phenyl-cyclopropyl,5-methylsulfonylthiophen-2-yl, 1,8dimethyl-6-hydroxy-bicyclo[2.2.2]oct-2-yl, 1,4-benzodioxan-2-yl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, cyclohex-3-enyl,3,5-difluorophenyl, 4-methylphenyl, 2-naphthyl, 1-naphthyl,4-chlorothiophene-yl, 4-cyanophenyl, tetrahydrofuran-2-yl,cyclohex-3-ene-yl, 1,2,3,4-tetrahydronaphth-2-yl,1,2,3,4-tetrahydronaphth-3-yl, 4-trifluoromethyl-cyclohexyl,bicyclo[2.2.1]hept-2-yl, bicyclo[2.2.1]hept-5-ene-2-yl, 2,2dichloropropyl, 2,4-dichlorophenyl, cis-2-methyl-cyclopropyl,1-(4-chlorophenyl)cyclobutyl, 2-phenylphenyl,1,2-dihydro-1-oxo-2-phenyl-bicyclo[3.3.1]non-6-ene-3-yl and —CH═CH(φ)).

Preferred R¹ groups include unsubstituted aryl groups such as phenyl,1-naphthyl, 2-naphthyl, etc.; substituted aryl groups such asmonosubstituted phenyls (preferably substituents at 3 or 5 positions);disubstituted phenyls (preferably substituents at 3 and 5 positions);and trisubstituted phenyls (preferably substituents at the 3,4,5positions). Preferably, the substituted phenyl groups do not includemore than 3 substituents. Examples of substituted phenyls include, forinstance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl,2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl,4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl,4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl,4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl,3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl,3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl,3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl,3-chloro-4-iodophenyl, 3,4-methylenedioxyphenyl, 4-azidophenyl,4-cyanophenyl, 4-ethylphenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl,4-(1-othoxy)ethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl,3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl,3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,2-fluoro-3-trifluoromethylphenyl.

Other preferred R¹ groups include, by way of example, adamantyl, benzyl,2-phenylethyl, 3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl,n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, —CH₂-cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂—cyclopentyl, pyrid-2-yl,pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl),chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl,benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl,thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl,2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl,6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl,2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetrazol-5-yl, allyl,2-(cyclohexyl)ethyl, (CH₃)₂CH═CHCH₂CH₂CH(CH₃)—, phenyl-C(O)CH₂—,thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl,2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, norboran-2-yl,(4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl,(3-methoxyphenyl)methyl, (3-hydroxyphenyl)methyl,(4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl,(4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl,(2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,(2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl,(1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH₃OC(O)CH₂—,benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl,3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl),methoxymethyl, CH₃CH═CH—, CH₃CH₂CH═CH—, (4-chlorophenyl)C(O)CH₂—,(4-fluorophenyl)C(O)CH₂—, (4-methoxyphenyl)C(O)CH₂—,4-(fluorophenyl)-NHC(O)CH₂—, 1-phenyl-n-butyl,(phenyl)₂-CHNHC(O)CH₂CH₂—, (CH₃)₂NC(O)CH₂—, (phenyl)₂CHNHC(O)CH₂CH₂—,methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH₂—,4-methoxyphenyl-C(O)CH₂—, phenyl-C(O)CH₂—, CH₃C(O)N(phenyl)-, ethenyl,methylthiomethyl, (CH₃)₃CNHC(O)CH₂—, 4-fluorophenyl-C(O)CH₂—,diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH₂—,benzo[b]thiophen-3-yl, (CH₃)₃COC(O)NHCH₂—, trans-styryl, H₂NC(O)CH₂CH₂—,2-trifluoromethylphenyl-C(O)CH₂, C(O)NHCH(phenyl)CH₂—, mesityl,CH₃CH(═NHOH)CH₂—, 4-CH₃-phenyl-NHC(O)CH₂CH₂—, C(O)CH(phenyl)CH₂—,(CH₃)₂CHC(O)NHCH(phenyl)-, CH₃CH₂OCH₂—, CH₃OC(O)CH(CH₃)(CH₂)₃—,2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH₃-benzofuran-3-yl,2-(2,4-dichlorophenoxy)ethyl, phenyl-SO₂CH₂—, 3-cyclohexyl-n-propyl,CF₃CH₂CH₂CH₂— and N-pyrrolidinyl.

Still other preferred R¹ groups include those set forth in the Tablesbelow.

Each R² is preferably (and independently for n=2) selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl,heteroaryl and heterocyclic.

Particularly preferred R² substituents include, by way of example,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, —CH₂CH(CH₂CH₃)₂, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl,benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl,3-methylpentyl, —CH₂-cyclopropyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclohexyl, —CH₂-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,p-(N-morpholino-CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol-4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thiophen-2-yl,—CH₂(1-methyl)cyclopropyl, —CH₂-thiophen-3-yl, thiophen-3-yl,thiophen-2-yl, —CH₂-C(O)O-t-butyl, —CH₂—C(CH₃)₃, —CH₂CH(CH₂CH₃)₂,-2-methylcyclopentyl, -cyclohex-2-enyl, —CH[CH(CH₃)₂]COOCH₃,—CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═C , —CH₂CH═CHCH₃ (cis and trans), —CH₂OH,—CH(OH)CH₃, —CH(O-t-butyl)CH₃, —CH₂OCH₃, —(CH₂)₄NH-Boc, —(CH₂)₄NH₂,—CH₂-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl(2-pyridyl, 3-pyridyl and 4-pyridyl), —CH₂-naphthyl (e.g., 1-naphthyland 2-naphthyl), —CH₂-(N-morpholino), p-(N-morpholino-CH₂CH₂O)-benzyl,benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl,4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl,6-methoxynaphth-2-yl, —CH₂CH₂SCH₃, thien-2-yl, and thien-3-yl.

Compounds of this invention include, by way of example,

3-[(N′-(4-methylbenzoyl)-D-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(4-methylbenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(2-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(1-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(5-Chloro-2-thiophenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(4-Cyanobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(Acetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-phenoxybutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Thiophenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2,3-Diphenylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((R,S)-(−)-α-Methoxyphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Cyclohexanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-(4-Chlorophenoxy)-2-methylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Cyclobutanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(1-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Benzofurancarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Isopropyl-2-phenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(5-Chlorobenzofuran-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Ethylhexanoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Methylbutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((R,S)-2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(5,5-dimethyl-butyrolactone-4-yl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Methyl-4,4,4-trifluorobutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

5-{N′-(2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(tetrahydro-3-furoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

3-[N′-(3,5-difluorophenyl-α-methoxyacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one

3-[N′-(3,5-difluorophenyl-α-methoxyacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one

(S)-3-[(N′-(4-(Trifluoromethyl)cyclohexanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Bicyclo(2.2.1)hept-5-ene-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2,2-Dichlorocyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Cycloheptanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Methylvaleryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(2-(4-hydroxyphenoxy)propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(α-(Hydroxymethyl)phenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(1-(2,4-Dichlorophenyl)cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Ethylbutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Methylcyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(1-(4-Chlorophenyl)-1-cyclobutanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-Biphenylcarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Pivalyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(trans-Cinnamyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(1,2-Dihydro-1-oxo-2-phenyl-4-isoquinolinecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Bicyclo(3.3.1)non-6-ene-3-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(3-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-(4-Cyanophenoxy)-2-methylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Tetrahydro-2-ftiroyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-(4-trifluorophenyoxy)propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(2-(4-Biphenylyloxy)propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Diphenylacetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(4-(methylsulfonyl)benzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(4-chloro-α-methylphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(trans-2-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(4-chloro-(α,α-dimethylphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(5-methylsulfonyl)thiophene-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(1,8-dimethyl-6-Hydroxy-bicyclo(2.2.2)octane-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((S)-(+)-2-hydroxy-2-phenylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(1,4-Benzodioxan-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Tetrahydro-3-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Acetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(3-Cyclohexenecarboxyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(Cyclopropanecarboxyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(3,5-Difluorobenzoyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[(N′-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

3-[(N′-(trans-cinnamyl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

3-[(N′-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

3-[(N′-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(α-hydroxy-diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

3-[(N′-(3,5-difluorobenzoyl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

3-[(N′-(L-2-pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-(α-hydroxy-diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-2-(diethylamino)ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

3-[(N′-(1-phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

3-[(N′-(α-methoxyphenylacetyl)-L-alaninyl)]amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

3-(S)-[2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-methyl-acetyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-(S)-[2-((1H)-isoquinoline-3,4-dihydro-3-oxo)-2-methyl-acetyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((trans-2-Phenylcyclopropyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((3,4-Dichlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-propenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((R)-(−)-1-(1-Naphthyl)ethyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2,6-Diisopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((3-[(Trifluoromethyl)phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((Phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((4-ethoxycarbonylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-Bromophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((o-Tolyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-Ethyl-6-methylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-Fluorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2,4-difluorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-Ethoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((3-Acetylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((3-[(cyano)phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((Phenethyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((4-n-Butylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((Octyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((4-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((4-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((Hexyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-Isopropylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2,6-Difluorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((Octadecyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((4-(Trifluoromethoxy)phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2,4-Dichlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((3-Ethoxycarbonylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((4-Chlorophenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((4-butoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((4-Phenoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((1-Naphthyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-Biphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-(Methylthio)phenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-Ethylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((3-Methoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((3,4,5-Trimethoxyphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2,4,6-Trimethylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-methyl-6-t-butylphenyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-[(N′-((2-(2-thiophene-yl)ethyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

3-[N′-3,5-difluorophenyl-acetamido)-L-alaninyl]-3-amino-2,3-dihydro1-methyl-5-phenyl-1H-1,4-benzodiazepine

3-[N′-3,5-difluorophenyl-α-azidoacetyl)-L-alaninyl]-3-amino-2,3-dihydro1-methyl-5-phenyl-1H-1,4-benzodiazepine

5-{N′-(cyclopropanecarboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(2-methylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-((aminoacetoxy)-3,5-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

3-[N′-(3,5-difluorophenyl-α-(2-aminoacetoxy)acetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one

5-{N′-(diphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(trans-cinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(tetrahydro-2-furoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(cyclopentanecarboxyl)L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(2-thiophenecarboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-((S)-(+)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-((R)-(−)-2-hydroxy-2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

3-[N′-(3,5-difluorophenyl-α-hydroxy-α-methylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one

5-{N′-(benzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

3-[N′-(3,5-difluorophenyl-α-hydroxy-α-methylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one

5-{N′-(3-fluorobenzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((Butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((Benzylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(benzylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((Ethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((Phenethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(3,5-difluorophenyl-α-aminoacetyl)-L-valinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

-(S)-(N′-(3,5-difluorophenyl-α-aminoacetyl)-L-tert-leucinyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(butylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(octylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((2-(thiophen-2-yl)ethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(3,5-difluorophenyl-α-aminoacetyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(L-valinyl)-L-alaninyl-)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

5-(R/S)-(N′-(2-hydroxy-2-phenethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((hexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((cyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((isopropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((tert-butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((1-adamantylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((2-methylpropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(R/S)-3-hydroxy-3-phenylethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-((3-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-((N′-(S)-1-hydroxymethyl-3-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-((N′-(1S)-(2S)-1-hydroxymethyl-2-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(3chloropropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-octylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-1,1,3,3-tetramethylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(R/S)-1-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-((N′-(R/S)-1-hydroxymethylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-((N′-(R/S)-1,3-dimethylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-((N′-(R)-1-hydroxymethyl-3-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-((N′-(R/S)-2-methylbutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-morpholinoureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(2-(2-hydroxyethoxy)-ethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-piperidinylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(N″-methyl-N″-butylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(1-(R/S)-hydroxymethylcyclopentylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(4-hydroxybutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N-(1-(R/S)-hydroxymethyl-2-methylpropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(2-(R/S)-hydroxycyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(isopropyl-hydroxyureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(benzyl-hydroxyureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(3,5-difluorophenyl-α-aminoacetyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(3,5-difluorophenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(threonine)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(D-valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N″-(S)-phenylglycinyl)-N′-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one

5-(S)-[(N″-L-valinyl)-N′-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one

5-(S)-(N′-(thiomorpholinylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(2(R/S)-hydroxybutylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-2,2,2-trifluoroethylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(4R/S)-cyclohexylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N′-(1R)-hydroxymethyl-3-methylthiopropylureylenyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-hydroxy-2-methylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-{N′-(2-hydroxy-2-methylbutanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

3-[N′-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

5-(S)-[N′-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-[N′-(L-Trifluoromethylphenylglycinyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-[N′-(L-N-methyl-valinyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-(N″-(3,5-difluorophenylglycinyl)-N′-L-alaninyl]amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepinehydrochloride

5-(S)-(N″-(3,5-difluorophenylglycinyl)-N′-L-alaninyl]amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepinehydrochloride

5-(S)-[N′-(Hexafluorovalinyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

3-[N′-(2-mercapto-3-methyl-butanoyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

5-(S)-[N′-(2-mercapto-3-methylbutanoyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Additional examples of suitable compounds include:

5-(S)-[N′-(2-Amino-3,3,3-trifluoromethylbutyryl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-[N′-(2-amino-5,5,5-trifluoropentanyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

5-(S)-[N′-(2-amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

1-(S)-[N′-(2-Amino-3,3,3-trifluorobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

1-(S)-[N′-(2-Amino-5,5,5-trifluoropentanoyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

1-(S)-[N′-(2-Amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

1-(S)-[N′-(2-Aminobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

1-(S)-[N′-(Hexafluorovalinyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

1-(S)-[N′-(L-2-Aminobutyryl)-L-alaninyl]-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

Preferred cyclic groups defined by W and —C(H)_(p)C(═X)— includecycloalkyl, lactone, lactam, benzazepinone, dibenzazepinone andbenzodiazepine groups. In one preferred embodiment, the cyclic groupdefined by W and —C(H)_(p)C(═X)—, forms a cycloalkyl group of theformula:

wherein T is selected from the group consisting of alkylene andsubstituted alkylene.

A preferred cycloalkyl group is represented by the formula:

wherein each V is independently selected from the group consisting ofhydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, substituted amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; each R^(a) is independentlyselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl,cyano, halo, and the like; t is an integer from 0 to 4; and w is aninteger from 0 to 3.

Preferably t is an integer from 0 to 2 and, more preferably, is aninteger equal to 0 or 1.

In another preferred embodiment, the cyclic group defined by W, togetherwith —C(H)_(p)C(═X)— is a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R²¹— and —ZR²¹—, where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

Particularly preferred alcohol or thiol substituted groups include

wherein each V is independently selected from the group consisting ofhydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, substituted amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxyalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; each R^(a) is independentlyselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino, carboxyl, carboxyalkyl,cyano, halo, and the like; t is an integer from 0 to 4; and w is aninteger from 0 to 3.

Preferably t is an integer from 0 to 2 and, more preferably, is aninteger equal to 0 or 1.

Yet another preferred embodiment of the cyclic group defined by W,together with —C(H)_(p)C(═X)—, is a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R²¹— and —ZR²¹—, where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

Particularly preferred cyclic ketone and thioketone groups include:

wherein each V is independently selected from the group consisting ofhydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; each R^(a) is independentlyselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl,cyano, halo, and the like; t is an integer from 0 to 4; and w is aninteger from 0 to 3.

Preferably t is an integer from 0 to 2 and, more preferably, is aninteger equal to 0 or 1.

In another preferred embodiment, the cyclic group defined by W, togetherwith —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R²¹— and —ZR²¹—, where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

Particularly preferred lactone and thiolactone groups include:

wherein each V is independently selected from the group consisting ofhydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; each R^(a) is independentlyselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino carboxyl, carboxyl alkyl,cyano, halo, and the like; t is an integer from 0 to 4; and w is aninteger from 0 to 3.

Preferably t is an integer from 0 to 2 and, more preferably, is aninteger equal to 0 or 1.

In another preferred embodiment, the cyclic group defined by W and—C(H)_(p)C(═X)—, forms a lactam ring of the formula:

or a thiolactam ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R²¹— and —ZR²¹—, where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

Particularly preferred lactam and thiolactam groups include:

wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene and —N═CH—; Qis oxygen or sulfur; each V is independently selected from the groupconsisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, substituted amino aminoacyl, alkaryl, aryl, aryloxy,carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy,substituted thioalkoxy, trihalomethyl and the like; each R^(a) isindependently selected from the group consisting of alkyl, substitutedalkyl, alkoxy, substituted alkoxy, amino, substituted amino carboxyl,carboxyl alkyl, cyano, halo, and the like; R^(b) is selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl,heteroaryl, heterocyclic, and the like; R^(c) is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,aryl, heteroaryl, heterocyclic, thioalkoxy, substituted amino,cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; tis an integer from 0 to 3; and w is an integer from 0 to 3.

Preferably t is an integer from 0 to 2 and, more preferably, is aninteger equal to 0 or 1.

In one preferred embodiment of this invention, W is a cyclic group ofthe formula:

wherein

each R⁶ is independently selected from the group consisting of acyl,acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino,substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl,cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl,heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioheteroaryloxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, and—SO₂-heteroaryl;

each R⁷ is independently selected from the group consisting of acyl,acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substitutedalkoxy, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino,substituted amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyalkyl,cyano, cycloalkyl, substituted cycloalkyl, halo, heteroaryl,heterocyclic, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioheteroaryloxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, and—SO₂-heteroaryl;

R⁸ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl,aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl and heterocyclic;

p is an integer from 0 to 4; q is an integer from 0 to 4.

Preferably, R⁶ and R⁷ are independently selected from the groupconsisting of alkoxy, substituted alkoxy, alkyl, substituted alkyl,amino, substituted amino, carboxyl, carboxyalkyl, cyano, halo, nitro,thioalkoxy and substituted thioalkoxy. More preferably, when present, R⁶and R⁷ are fluoro.

R⁸ is preferably selected from the group consisting of hydrogen, alkyl,substituted alkyl, acyl, aryl, cycloalkyl and substituted cycloalkyl.More preferably, R⁸ is selected from the group consisting of hydrogen,alkyl, substituted alkyl and cycloalkyl.

Particularly preferred R⁸ substituents include, by way of example,hydrogen, methyl, 2-methypropyl, hexyl, methoxycarbonylmethyl,3,3-dimethyl-2-oxobutyl, 4-phenylbutyl, cyclopropylmethyl,2,2,2-trifluoroethyl, cyclohexyl, and the like.

In another preferred embodiment of this invention, W is a cyclic groupof the formula:

wherein R⁶, R⁷, and p are as defined herein and r is an integer from 0to 3.

In still another preferred embodiment of this invention, W is a cyclicgroup of the formula:

wherein R⁶ and p are as defined herein.

In yet another preferred embodiment of this invention, W is a cyclicring of the formula:

wherein R⁶ and p are as defined herein.

In still another preferred embodiment of this invention, W is a cyclicring of the formula:

wherein R⁶, R⁸ and p are as defined herein; and

each R⁹ is independently selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, heteroaryl and heterocyclic; and g is aninteger from 0 to 2.

When present, R⁹ is preferably alkyl or substituted alkyl.

In another preferred embodiment of this invention, W is a cyclic ring ofthe formula:

wherein R⁶, R⁸, R⁹, g and p are as defined herein.

In yet another preferred embodiment of this invention, W is a cyclicring of the formula:

wherein R⁶, R⁸, R⁹, g and p are as defined herein.

In still another preferred embodiment of this invention, W is a cyclicring of the formula:

wherein R⁶, each R⁸ and p are as defined herein.

In another preferred embodiment of this invention, W is a cyclic ring ofthe formula:

wherein R⁶, each R⁸, R⁹, g and p are as defined herein.

In another preferred embodiment of this invention, W is a cyclic ring ofthe formula:

wherein R⁶, R⁸ and p are as defined herein; and

R¹⁰ is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substitutedamino, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, heteroaryl, heterocyclic, thioalkoxy andsubstituted thioalkoxy.

In another preferred embodiment of this invention, W is a cyclic ring ofthe formula:

wherein R⁶, R¹⁰ and p are as defined herein; and

D—E is selected from the group consisting of alkylene, alkenylene,substituted alkylene, substituted alkenylene and —N═CH—.

In another preferred embodiment of this invention, W is a cyclic ring ofthe formula:

wherein R⁶, R⁸, R⁹, g and p are as defined herein; and

Q is oxygen, sulfur, —S(O)— or —S(O)—.

In another preferred embodiment of this invention, W is a cyclic ring ofthe formula:

wherein R⁶, R⁸ and p are as defined herein.

In another preferred embodiment of this invention, W is a cyclic ring ofthe formula:

wherein R⁸ is as defined herein.

In the above formulae, preferably each R⁶ is independently selected fromthe group consisting of alkyl, substituted alkyl, alkoxy and halo; eachR⁷ is independently selected from the group consisting of alkyl,substituted alkyl, alkoxy and halo; each R⁸ is independently selectedfrom the group consisting of alkyl, substituted alkyl, cycloalkyl andaryl; each R⁹ is independently selected from the group consisting ofalkyl, substituted alkyl, cycloalkyl and aryl; and g, p, q and r are 0or 1. More preferably, g, p, q and r are 0.

In another preferred embodiment, the cyclic group defined by W, togetherwith —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R²¹— and —ZR²¹—, where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

A still further preferred embodiment is directed to a ring group definedby W, together with —C(H)_(p)C(═X)—, of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R²¹— and —ZR²¹—, where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

In another preferred embodiment, R¹⁵ is H, R¹ is alkyl or aryl, Rb isalkyl, substituted alkyl, cycloalkyl or aryl, R² is methyl, and thecompound is a compound of Formulas I, II or VI.

This invention also provides for novel pharmaceutical compositionscomprising a pharmaceutically inert carrier and one or more of thecompounds described in Formulas I-VI above.

Still further, this invention provides for novel compounds of FormulasI-VI:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic;

R′ is selected from the group consisting of aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heteroaryl, heterocyclic, —CH₃, —CH═CH₂, —CH═CHR¹, —CH═CR¹R¹, —CR¹═CH₂,—CR¹═CHR¹, —CR¹═CR¹R¹, —C═CH and —C═CR¹; with the proviso that when R′is heteroaryl or heterocyclic, there is no N in R′ at a position beta tothe C═Q group;

Q is S or O;

R¹⁵ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, heterocyclic and heteroaryl;

R¹⁵′ is selected from the group consisting of hydrogen, hydroxyl, alkyl,substituted alkyl, aryl, heterocyclic and heteroaryl;

W, together with —C(H)_(p)C(═X)—, forms a cycloalkyl, cycloalkenyl,heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl groupwherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substitutedcycloalkyl or substituted cycloalkenyl group is optionally fused to forma bi- or multi-fused ring system (preferably no more than 5 fused rings)with one or more ring structures selected from the group consisting ofcycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which,in turn, each of such ring structures are optionally substituted with 1to 4 substituents selected from the group consisting of hydroxyl, keto,thioketo, halo, alkoxy, substituted alkoxy, thioalkoxy, substitutedthioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, substituted amino, —NHC(O)R⁴, —NHSO₂R⁴, —C(O)NH₂, —C(O)NHR⁴,—C(O)NR⁴R⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NHR⁴ and —S(O)₂NR⁴R⁴, where each Ris independently selected from the group consisting of alkyl,substituted alkyl, aryl and heteroaryl;

X is selected from the group consisting of oxo (═O), thiooxo (═),hydroxyl (—H, —OH), thiol (H, —SH) and hydro (H,H);

Y is represented by the formula:

 wherein each R² is independently selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;

Z is represented by the formula —T—C(X′)(X″)C(O)— where T is selectedfrom the group consisting of a bond covalently linking R¹ to—C(X′)(X″)—, oxygen, sulfur, and —NR⁵ where R⁵ is hydrogen, acyl, alkyl,substituted alkyl, aryl, heterocyclic or heteroaryl group;

R^(5′) is hydrogen, alkyl, substituted alkyl, aryl, heterocyclic orheteroaryl group;

X′ and X″ are independently selected from the group consisting ofhydrogen, fluoro, alkyl, substituted alkyl, aryl, heteroaryl,heterocyclic, —OR⁵′, —SR⁵, —N(R⁵)₂, —N(CO)OR¹⁵ and —N₃, with the provisothat at least one of X′ or X″ is other than hydrogen, hydroxy or fluoro,and with the further proviso that both X′ and X″ cannot both be —OR⁵′,—SR⁵, —N(R⁵)₂, —N(CO)OR¹⁵ and —N₃; further, neither X′ and X″ can be—OR^(5′), —SR⁵, —N(R⁵)₂, —N(CO)OR¹⁵ or —N₃ when T is other than a bondcovalently linking R¹ to —C(X′)(X″)—;

n is an integer equal to 1 or 2;

p is an integer equal to 0 or 1 such that when p is zero, the ringdefined by W and —C(H)_(p)C(═X)— is unsaturated at the carbon atom ofring attachment to Y and when p is one, the ring is saturated at thecarbon atom of ring attachment to Y,

with the following provisos:

when R1 is 2-propylpentanoyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, thenW, together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15is hydrogen, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is α-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen,then W, together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is α-methoxyphenylacetyl, R2 is methyl, and R15 is hydrogen,then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is α-hydroxy-diphenylacetyl, R2 is methyl, and R15 is hydrogen,then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is 2-(chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15 ishydrogen, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is diphenylacetyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is 3,5-difluorobenzoyl, R2 is methyl, and R15 is hydrogen, thenW, together with >CH and >C═X, does not form a2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is trans-cinnamyl, R2 is methyl, and R15 is hydrogen, then W,together with >CH and >C═X, does not form a2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1 is 2-(4-chlorophenoxy)-2-methylpropionyl, R2 is methyl, and R15is hydrogen, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

when R1—N(R¹⁵) is (2,5-dimethoxyphenyl)ureylenyl and R2 is methyl, thenW, together with >CH and >C═X, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

when R1 is D,L-2-pyrrolidinone-5-yl, R2 is methyl, and R15 is hydrogen,then W, together with >CH and >C═X, does not form a7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

As is appreciated by the skilled person, compounds of the presentinvention exist as isomers. Herein, the Cahn-Prelog-Ingold designationsof (R)- and (S)- and, for amino acid derived portions of the compounds,the L- and D- designations of stereochemistry relative to the isomers ofglyceraldehyde are used to refer to specific isomers where designated.The specific isomers can be prepared by stereospecific synthesis or canbe resolved and recovered by techniques known in the art, such as,chromatography on chiral stationary phases, and fractionalrecrystallization of addition salts formed by reagents used for thatpurpose. Useful methods of resolving and recovering specificstereoisomers are known in the art and described, for example, inStereochemistry of Organic Compounds, E. L. Eliel and S. H. Wilen(Wiley-Interscience 1994), Enantiomers, Racemates and Resolutions, J.Jacques, A. Collet and S. J. Wilen (Wiley-Interscience 1981), andEuropean Patent Application No. EP-A-838448, published Apr. 29, 1998. Itis to be understood that the invention extends to all of the isomericforms of the compounds of the present invention, including thediastereomeric, enantiomeric and racemic forms of the compounds.

Preferred compounds described herein include those set forth in thetables below:

TABLE 1-1

Ex. R R¹ R² R³ 1-1 2-thiophene-yl methyl phenyl methyl 1-2 2-furanylmethyl phenyl methyl 1-3 cyclobutyl methyl phenyl methyl 1-4 1-phenylmethyl phenyl methyl cyclopropyl 1-5 cyclohexyl methyl phenyl methyl 1-62-benzofuranyl methyl phenyl methyl 1-7 5-chloro methyl phenyl methylbenzofuran-2-yl 1-8 5,5-dimethyl- methyl phenyl methyl butyrolactone-4-yl 1-9 3-furoyl methyl phenyl methyl 1-10 4-methyl methyl phenylmethyl sulfonyl phenyl 1-11 cis-2-phenyl methyl phenyl methyl 1-125-methyl methyl phenyl methyl sulfonyl thiophen-2-yl 1-131,8-dimethyl-6- methyl phenyl methyl hydroxy- bicyclo[2.2.2]- oct-2-yl1-14 1,4-benzo methyl phenyl methyl dioxan-2-yl 1-15 tetrahydro methylphenyl methyl furan-3-yl 1-16 cyclohex-3-ene- methyl phenyl phenyl yl1-17 cyclopropyl methyl phenyl phenyl 1-18 3,5-difluoro methyl phenylphenyl phenyl 1-19 2- methyl 2-pyridyl methyl pyrrolidinone- 1-211-phenyl methyl 2-pyridyl methyl 1-22 1-phenyl 2-oxo-3,3- 2-pyridylmethyl cyclopropyl dimethylbutyl 1-23 3,5- 2-oxo-3,3- 2-pyridyl methyldifluorophenyl dimethylbutyl 1-24 2- 2-oxo-3,3- 2-pyridyl methylpyrrolidinone- dimethylbutyl 5-yl 1-26 1-phenyl 2-diethyl 2-pyridylmethyl cyclopropyl aminoethyl 1-27 4-methylphenyl methyl phenyl phenyl1-28 4-methylphenyl methyl phenyl methyl 1-29 3-pyridyl methyl phenylmethyl 1-30 2-naphthyl methyl phenyl methyl 1-31 1-naphthyl methylphenyl methyl 1-32 4-chloro- methyl phenyl methyl thiophene-yl 1-334-cyanophenyl methyl phenyl methyl 1-34 tetrahydrofuran- methyl phenylmethyl 2-yl 1-35 3,5-difluoro methyl phenyl methyl phenyl 1-36cyclohex-3-ene- methyl phenyl methyl yl 1-37 1,2,3,4- methyl phenylmethyl tetrahydro naphth-2-yl 1-38 cyclopentyl methyl phenyl methyl 1-394-trifluoro methyl phenyl methyl methyl cyclohexyl 1-40 bicyclo[2.2.1]methyl phenyl methyl hept-2-yl 1-41 bicyclo[2.2.1] methyl phenyl methylhept-5-ene-2-yl 1-42 2,2-dichloro methyl phenyl methyl cyclopropyl 1-43cycloheptyl methyl phenyl methyl 1-44 1-(2,4-dichloro methyl phenylmethyl phenyl)- cyclopropyl 1-45 cis-2-methyl methyl phenyl methylcyclopropyl 1-46 1-(4-chloro methyl phenyl methyl phenyl) cyclobutyl1-47 2-phenylphenyl methyl phenyl methyl 1-48 1,2-dihydro-1- methylphenyl methyl oxo-2-phenyl- 4-isoquinolinyl 1-49 bicyclo[3.3.1]- methylphenyl methyl non-6-ene-3-yl 1-50 cyclopropyl methyl phenyl methyl 1-51tetrahydro methyl phenyl methyl furan-2-yl 1-52 3,5-difluoro methylphenyl methyl phenyl 1-53 cyclohex-3-ene- methyl phenyl methyl yl 1-541,2,3,4- methyl phenyl methyl tetrahydro naphth-3-yl 1-55 cyclopentylmethyl phenyl methyl

TABLE 1-2

Ex. R 1-56 tetrahydrofuran-3-yl 1-57 cyclopropyl 1-59bicyclo[2.2.1]heptan-2- yl 1-60 tetrahydrofuran-2-yl 1-61 cyclopentyl1-62 thiophene-2-yl

TABLE 2-1

Ex. R X¹ X² R¹ R² R³ 2-1 benzyl phenyl H methyl phenyl methyl 2-2 phenylethyl H methyl phenyl methyl 2-4 phenyl isopropyl H methyl phenyl methyl2-5 butyl ethyl H methyl phenyl methyl 2-6 ethyl methyl H methyl phenylmethyl 2-7 2,2,2- methyl H methyl phenyl methyl trifluoro ethyl 2-8phenyl phenyl H methyl phenyl phenyl 2-9 4-chloro methyl H methyl phenylmethyl phenyl 2-10 4-chloro methyl methyl methyl phenyl methyl phenyl2-11 phenyl methyl hydroxyl methyl phenyl methyl 2-12 phenyl phenylhydroxyl methyl 2-pyridyl methyl 2-15 phenyl phenyl hydroxyl 2-oxo-3,3-2-pyridyl methyl 2-17 phenyl phenyl hydroxyl 2-diethyl 2-pyridyl methylamino ethyl 2-18 3,5- methyl hydroxyl methyl phenyl methyl difluorophenyl 2-19 3,5- methyl hydroxyl methyl phenyl methyl difluoro phenyl

TABLE 2-2

Ex R R¹ X¹ X² 2-20 phenyl methyl phenyl H 2-21 H methyl H H 2-22 propylmethyl methyl H 2-23 phenyl methyl hydroxymethyl H 2-24 ethyl methylethyl H 2-25 methyl methyl methyl methyl 2-26 phenyl methyl phenyl H2-27 H phenyl H H 2-28 isopropyl methyl thioacetyl H 2-29 isopropylmethyl thio H

TABLE 2-3

Ex. R X¹ X² 2-30 phenyl methyl H 2-31 butyl methyl H 2-32 phenyl phenylH 2-33 phenyl methyl hydroxyl 2-34 phenyl hydroxyl methyl 2-35 methylhydroxyl methyl 2-36 ethyl hydroxyl methyl 2-37 isopropyl thioacetyl H2-38 H H H 2-39 isopropyl thiol H

TABLE 3-1

Ex. R¹ R² 3-1 phenyl methyl 3-2 2-pyridyl methyl

TABLE 3-2

Ex. R 3-5 Methyl

TABLE 4-1

Ex. R R¹ R² R³ R⁴ 4-1 phenyl methyl ethyl H phenoxy 4-2 phenyl methylphenyl H methoxy 4-3 phenyl methyl methyl methyl 4-chlorophenoxy 4-4phenyl methyl methyl H phenoxy 4-5 phenyl methyl 3,5- H methoxy difluorophenyl 4-6 phenyl methyl 3,5- H methoxy difluoro phenyl 4-7 phenylmethyl methyl H 4-hydroxyphenoxy 4-8 phenyl methyl methyl H 4-trifluoromethoxy phenoxy 4-9 phenyl methyl methyl H 4-phenylphenoxy 4-102-pyridyl 2-(diethyl phenyl H methoxy amino) ethyl 4-16 phenyl methylmethyl methyl 4-cyano phenoxy

TABLE 5-1

Ex. R R′ X 5-1 trans-2-phenylcyclopropyl H O 5-2 3,4-dichlorophenyl H O5-3 2-propenyl H O 5-4 (1-naphthyl)ethyl H O 5-5 2,6-diisopropylphenyl HO 5-6 3-[(trifluoromethyl)phenyl H O 5-7 phenyl H O 5-8(4-ethoxycarbonyl)phenyl H O 5-9 2-bromophenyl H O 5-10 o-tolyl H O 5-112-ethyl-6-methylphenyl H O 5-12 2-fluorophenyl H O 5-132,4-difluorophenyl H O 5-14 2-ethoxyphenyl H O 5-15 3-acetylphenyl H O5-16 3-[(cyano)phenyl H O 5-18 phenethyl H O 5-19 4-n-butylphenyl H O5-20 octyl H O 5-21 4-biphenyl H O 5-22 4-isopropylphenyl H O 5-23 hexylH O 5-24 2-isopropylphenyl H S 5-25 2,6-difluorophenyl H O 5-26octadecyl H O 5-27 4-(trifluoromethoxy)phenyl H O 5-282,4-dichlorophenyl H O 5-29 3-ethoxycarbonylphenyl H O 5-304-chlorophenyl H O 5-31 4-butoxyphenyl H O 5-32 4-phenoxyphenyl H O 5-331-naphthyl H O 5-34 2-biphenyl H O 5-35 2-(methylthio)phenyl H O 5-362-ethylphenyl H O 5-37 3-methoxyphenyl H O 5-38 3,4,5-trimethoxyphenyl HO 5-39 2,4,6-trimethylphenyl H O 5-40 2-methyl-6-t-butylphenyl H O 5-412-(2-thiophene-yl H O

TABLE 5-2

Ex. R R′ 5-43 (2-thiophene-yl)ethyl H 5-44 phenethyl H 5-45 butyl H 5-46benzyl H 5-47 ethyl H 5-48 2-hydroxy-2-phenethyl H 5-49 hexyl H 5-50cyclohexyl H 5-51 isopropyl H 5-52 t-butyl H 5-53 1-adamantyl H 5-542-methylpropyl H 5-55 3-hydroxy-3-phenylethyl H 5-56 3-methylbutyl H5-57 (S)-1-hydroxymethyl-3- H methylbutyl 5-58 (1S)-(2S)-1- Hhydroxymethyl-2- methylbutyl 5-59 3-chloropropyl H 5-60 octyl H 5-611,1,3,3-tetramethylbutyl H 5-62 (R/S)-1-methylbutyl H 5-635-(S)-((N′-(R/S)-1- H hydroxymethylbutyl 5-64 (R/S)-1,3-dimethylbutyl H5-65 (R)-1-hydroxymethyl-3- H methylbutyl 5-66 (R/S)-2-methylbutyl H5-67 morpholino H 5-68 2-(2-hydroxyethoxy)-ethyl H 5-69 piperidinyl H5-70 N″-methyl-N″-butyl H 5-71 1-(R/S)- H hydroxymethylcyclopentyl 5-724-hydroxybutyl H 5-73 1-(R/S)-hydroxymethyl-2- H 5-742-(R/S)-hydroxycyclohexyl H 5-75 isopropyl OH 5-76 1-(benzyl) OH 5-77thiomorpholinyl H 5-78 2(R/S)-hydroxybutyl H 5-79 2,2,2-trifluoroethyl H5-80 (4R/S)-cyclohexyl H 5-81 hydroxymethyl-3- H methylthiopropyl

TABLE 6-1

Ex. R R′ 6-1 phenyl H 6-2 3-fluorophenyl H 6-3 benzyl H 6-4 butyl H 6-5octyl H

TABLE 7-1

Ex. R R′ R″ 7-1 3,5- NH₂ isopropyl difluorophenyl 7-2 3,5- NH₂ t-butyldifluorophenyl 7-3 isopropyl NH₂ methyl 7-4 phenyl NH₂ methyl 7-53,5-difluoro NH₂ methyl (Isomer A) phenyl 7-6 3,5-difluoro NH₂ methyl(Isomer B) phenyl 7-8 isopropyl NH₂ methyl 7-9 phenyl NH₂ methyl 7-103,5- NH₂ methyl (Mixture of difluorophenyl isomers) 7-11 phenylCF₃C(O)NH— methyl 7-12 isopropyl NHCH₃ methyl 7-13 1-trifluoro NH₂methyl methyl-2,2,2- trifluoroethyl

TABLE 7-2

Ex. R R′ 7-15 isopropyl —NH₂

TABLE 7-3

Ex. R R′ 7-17 phenyl NH₂ 7-18 isopropyl NH₂

TABLE 7-4

Ex. R R′ 7-19 3,5-difluoro NH₂—HCl phenyl 7-20 3,5-difluoro NH₂—HClphenyl

TABLE 7-5

Ex. R. 36361 1-trifluoromethyl ethyl 36362 3,3,3-trifluoropropyl 363632,2,2-trifluoroethyl

TABLE 7-6

Ex. R R¹ 36364 1-trifluoromethyl ethyl methyl 363653,3,3-trifluoropropyl methyl 36366 2,2,2-trifluoroethyl methyl 36367ethyl methyl 36368 1-(trifluoromethyl)-2,2,2- methyl trifluoroethyl36369 ethyl isobutyl

TABLE 8-1

Ex. R 8-1 3,5-difluorophenyl

TABLE 9-1

Ex. R′ 9-1 methyl

TABLE 9-2

Ex. R 9-2 methyl

TABLE 10-1

Ex. R 10-1 3,5- difluorophenylmethyl

TABLE 10-2

Ex. R R′ 10-2 methyl phenyl

Also included within the scope of this invention are prodrugs of thecompounds of Formulas I-VI described above including acylated forms ofalcohols and thiols, aminals of one or more amines, and the like, aswell as acid addition salts of amines. This invention is not intended toencompass subject matter disclosed and claimed in co-pending U.S. Ser.No. 08/996,422, the contents of which are hereby incorporated byreference in its entirety.

DETAILED DESCRIPTION OF THE INVENTION

As above, this invention relates to compounds that inhibit β-amyloidpeptide release and/or its synthesis, and, accordingly, have utility intreating Alzheimer's disease. However, prior to describing thisinvention in further detail, the following terms will first be defined.

Definitions

The term “β-amyloid peptide” refers to a 39-43 amino acid peptide havinga molecular weight of about 4.2 kD, which peptide is substantiallyhomologous to the form of the protein described by Glenner, et al.¹including mutations and post-translational modifications of the normalβ-amyloid peptide. In whatever form, the β-amyloid peptide is anapproximate 39-43 amino acid fragment of a large membrane-spanningglycoprotein, referred to as the β-amyloid precursor protein (APP). Its43-amino acid sequence is:

1

Asp Ala Glu Phe Arg His Asp Ser Gly Tyr

11

Glu Val His His Gln Lys Leu Val Phe Phe

21

Ala Glu Asp Val Gly Ser Asn Lys Gly Ala

31

Ile Ile Gly Leu Met Val Gly Gly Val Val

41

Ile Ala Thr (SEQ ID NO: 1)

or a sequence which is substantially homologous thereto.

“Alkyl” refers to monovalent alkyl groups preferably having from 1 to 20carbon atoms, more preferably 1 to 10 carbon atoms and most preferably 1to 6 carbon atoms. This term is exemplified by groups such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.

“Substituted alkyl” refers to an alkyl group, preferably of from 1 to 10carbon atoms, having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, keto,thioketo, carboxyl, carboxyalkyl, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl,—SO₂-heteroaryl, and mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono-and di-heterocyclic amino, and unsymmetric di-substituted amines havingdifferent substituents selected from alkyl, substituted alkyl, aryl,heteroaryl and heterocyclic.

“Alkylene” refers to divalent alkylene groups preferably having from 1to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term isexemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

“Substituted alkylene” refers to an alkylene group, preferably of from 1to 10 carbon atoms, having from 1 to 3 substituents selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyacylamino, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxyalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl,heteroaryl, heterocyclic, heterocyclooxy, heterocyclooxy, nitro, andmono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono-and di-arylamino, mono- and di-heteroarylamino, mono- anddi-heterocyclic amino, and unsymmetric di-substituted amines havingdifferent substituents selected from alkyl, substituted alkyl, aryl,heteroaryl and heterocyclic. Additionally, such substituted alkylenegroups include those where 2 substituents on the alkylene group arefused to form one or more cycloalkyl, aryl, heterocyclic or heteroarylgroups fused to the alkylene group. Preferably, such fused cycloalkylgroups contain from 1 to 3 fused ring structures.

“Alkenylene” refers to divalent alkenylene groups preferably having from2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms. This termis exemplified by groups such as ethenylene (—CH═CH—), the propenyleneisomers (e.g., —CH₂CH═CH— and —C(CH₃)═CH—) and the like.

“Substituted alkenylene” refers to an alkenylene group, preferably offrom 2 to 10 carbon atoms, having from 1 to 3 substituents selected fromthe group consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyacylamino, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxyalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl,heteroaryl, heterocyclic, heterocyclooxy, nitro, and mono- anddi-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclicamino, and unsymmetric di-substituted amines having differentsubstituents selected from alkyl, substituted alkyl, aryl, heteroaryland heterocyclic. Additionally, such substituted alkylene groups includethose where 2 substituents on the alkylene group are fused to form oneor more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to thealkylene group.

“Alkaryl” refers to -alkylene-aryl groups where alkylene and aryl are asdefined herein. Such alkaryl groups are exemplified by benzyl, phenethyland the like.

“Alkoxy” refers to the group “alkyl-O—”, where alkyl is as definedabove. Preferred alkoxy groups include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” refers to the group “substituted alkyl-O—” wheresubstituted alkyl is as defined above.

“Alkylalkoxy” refers to the group “-alkylene-O-alkyl” where alkylene andalkyl are as defined above. Such groups include methylenemethoxy(—CH₂OCH₃), ethylenemethoxy (—CH₂CH₂OCH₃), n-propylene-iso-propoxy(—CH₂CH₂CH₂OCH(CH₃)₂), methylene-t-butoxy (—CH₂-O-C(CH₃)₃) and the like.

“Alkylthioalkoxy” refers to the group “-alkylene-S-alkyl” where alkyleneand alkyl are as defined above. Such groups include methylenethiomethoxy(—CH₂SCH₃), ethylenethiomethoxy (—CH₂CH₂SCH₃),n-propylene-thio-iso-propoxy (—CH₂CH₂CH₂SCH(CH₃)₂),methylenethio-t-butoxy (—CH₂SC(CH₃)₃) and the like.

“Alkenyl” refers to alkenyl groups preferably having from 2 to 10 carbonatoms and more preferably 2 to 6 carbon atoms and having at least 1 andpreferably from 1-2 sites of alkenyl unsaturation. Preferred alkenylgroups include ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂), iso-propenyl(—C(CH₃)═CH₂), and the like.

“Substituted alkenyl” refers to an alkenyl group as defined above havingfrom 1 to 3 substituents selected from the group consisting of alkoxy,substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, keto,thioketo, carboxyl, carboxyalkyl, thiol, thioalkoxy, substitutedthioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro,—SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl, and mono- anddi-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclicamino, and unsymmetric di-substituted amines having differentsubstituents selected from alkyl, substituted alkyl, aryl, heteroaryland heterocyclic.

“Alkynyl” refers to alkynyl groups preferably having from 2 to 10 carbonatoms and more preferably 2 to 6 carbon atoms and having at least 1 andpreferably from 1-2 sites of alkynyl unsaturation. Preferred alkynylgroups include ethynyl (—CH≡CH₂), propargyl (—CH₂C≡CH) and the like.

“Substituted alkynyl” refers to an alkynyl group as defined above havingfrom 1 to 3 substituents selected from the group consisting of alkoxy,substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, keto,thioketo, carboxyl, carboxyalkyl, thiol, thioalkoxy, substitutedthioalkoxy, aryl, heteroaryl, heterocyclic, heterocyclooxy, nitro,—SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl, and mono- anddi-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclicamino, and unsymmetric di-substituted amines having differentsubstituents selected from alkyl, substituted alkyl, aryl, heteroaryland heterocyclic.

“Acyl” refers to the groups alkyl-C(O)—, substituted alkyl-C(O)—,cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, aryl-C(O)—,heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclicare as defined herein.

“Acylamino” refers to the group —C(O)NRR where each R is independentlyhydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclicwherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic areas defined herein.

“Substituted amino” refers to the group —N(R)2, where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, cycloalkyl, substituted cycloalkyl, heteroaryl,heterocyclic and where both R groups are joined to form a heterocyclicgroup. When both R groups are hydrogen, —N(R)2 is an amino group.Examples of substituted amino groups include, by way of example, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and diheteroarylamino, mono and di-heterocyclicamino, and unsymmetric di-substituted amines having differentsubstituents selected from the group consisting of alkyl, substitutedalkyl, aryl, heteroaryl, heterocyclic and the like.

“Aminoacyl” refers to the group —NRC(O)R where each R is independentlyhydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclicwherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic areas defined herein.

“Aminoacyloxy” refers to the group —NRC(O)OR where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,cycloalkyl-C(O)O—, aryl-C(O)O—, heteroaryl-C(O)O—, andheterocyclic-C(O)O— wherein alkyl, substituted alkyl, cycloalkyl, aryl,heteroaryl, and heterocyclic are as defined herein.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed (fused) rings (e.g., naphthyl or anthryl). Preferred arylsinclude phenyl, naphthyl and the like. Unless otherwise constrained bythe definition for the aryl substituent, such aryl groups can optionallybe substituted with from 1 to 5 substituents and preferably 1 to 3substituents selected from the group consisting of acyloxy, 1 to 5 andpreferably 1 to 3 substituents selected from the group consisting ofhydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl, amino,substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido,carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl, trihalomethyl.Preferred substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy.

“Aryloxy” refers to the group aryl-O— wherein the aryl group is asdefined above including optionally substituted aryl groups as alsodefined above.

“Carboxyalkyl” refers to the group “—C(O)O-alkyl” and“—C(O)O-substituted alkyl” where alkyl and substituted alkyl are asdefined above.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 12 carbon atomshaving a single cyclic ring or multiple condensed rings. Such cycloalkylgroups include, by way of example, single ring structures such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like, or multiple ring structures such asadamantanyl, bicyclo[2.2.1]heptyl, bicyclo(2.2.1)hept-5-ene-yl,bicyclo(3.3.1)non-6-ene-3-carboxyl) and the like.

“Substituted cycloalkyl” refers to cycloalkyl groups having from 1 to 5(preferably 1 to 3) substituents selected from the group consisting ofhydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, substituted amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxyalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like.

“Cycloalkenyl” refers to cyclic alkenyl groups of from 4 to 12 carbonatoms having at least one cyclic ring and preferably no more than fourrings, which rings are optionally fused, and which include at least onepoint of internal unsaturation. Examples of suitable cycloalkenyl groupsinclude, for instance, cyclobut-2-enyl, cyclopent-3-enyl,cyclooct-3-enyl and the like.

“Substituted cycloalkenyl” refers to cycloalkenyl groups having from 1to 5 substituents selected from the group consisting of hydroxy, acyl,acyloxy, alkyl, substitute d alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, substitutedamino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano,halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,trihalomethyl and the like.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either fluoro or chloro.

“Heteroaryl” refers to an aromatic carbocyclic group of from 1 to 15carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen andsulfur within at least one ring (if there is more than one ring).

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted withfrom 1 to 5 substituents and preferably 1 to 3 substituents selectedfrom the group consisting of acyloxy, 1 to 5 and preferably 1 to 3substituents selected from the group consisting of hydroxy, acyl, alkyl,alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy,substituted alkenyl, substituted alkynyl, amino, substituted amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl, trihalomethyl.Preferred substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a singlering (e.g., pyridyl or furyl) or multiple condensed rings (e.g.,indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl,pyrrolyl and furyl.

“Heteroaryloxy” refers to “O-heteroaryl”, where heteroaryl is as definedherein.

“Heterocyclooxy” refers to “O-heterocyclic”, where heterocyclic is asdefined herein.

“Heterocycle” or “heterocyclic” refers to a monovalent saturated orunsaturated group having a single ring or multiple condensed rings, from1 to 15 carbon atoms and from 1 to 4 hetero atoms selected fromnitrogen, sulfur or oxygen within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents selected from the group consisting of alkyl,substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, halo,nitro, heteroaryl, thiol, thioalkoxy, substituted thioalkoxy,thioaryloxy, trihalomethyl, and the like. Such heterocyclic groups canhave a single ring or multiple condensed rings. Preferred heterocyclicsinclude morpholino, piperidinyl, and the like.

Examples of nitrogen heterocycles and heteroaryls include, but are notlimited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline,piperidine, piperazine, indoline, morpholino, piperidinyl,tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containingheterocycles.

“Oxyacylamino” refers to the group —OC(O)NRR where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Thioalkoxy” refers to the group —S-alkyl.

“Substituted thioalkoxy” refers to the group —S-substituted alkyl.

“Thioaryloxy” refers to the group aryl-S— wherein the aryl group is asdefined above including optionally substituted aryl groups also definedabove.

“Thioheteroaryloxy” refers to the group heteroaryl-S— wherein theheteroaryl group is as defined above including optionally substitutedaryl groups as also defined above.

As to any of the above groups that contain 1 or more substituents, it isunderstood, of course, that such groups do not contain any substitutionor substitution patterns which are sterically impractical and/orsynthetically non-feasible.

“Pharmaceutically acceptable salts” refers to pharmaceuticallyacceptable salts of a compound of Formulas I-VI which salts are derivedfrom a variety of organic and inorganic counter ions well known in theart and include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate and the like can be used as the pharmaceuticallyacceptable salt.

The term “protecting group” or “blocking group” refers to any groupwhich when bound to one or more hydroxyl, amino or carboxyl groups ofthe compounds (including intermediates thereof such as the aminolactams,aminolactones, etc.) prevents reactions from occurring at these groupsand which protecting group can be removed by conventional chemical orenzymatic steps to reestablish the hydroxyl, amino or carboxyl group.The particular removable blocking group employed is not critical andpreferred removable hydroxyl blocking groups include conventionalsubstituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl,benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group thatcan be introduced chemically onto a hydroxyl functionality and laterselectively removed either by chemical or enzymatic methods in mildconditions compatible with the nature of the product.

Preferred removable amino blocking groups include conventionalsubstituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ),and the like which can be removed by conventional conditions compatiblewith the nature of the product.

Preferred carboxyl protecting groups include esters such as methyl,ethyl, propyl, t-butyl etc. which can be removed by mild hydrolysisconditions compatible with the nature of the product.

Compound Preparation Amidation Chemistry

Compounds including amide linkages can be readily prepared byconventional amidation of a carboxyl acid as shown in reaction (1) belowwhere, for the sake of illustration, n is one:

wherein R¹, R², W, X, and Z are as defined above. The reaction isconventionally conducted by using at least a stoichiometric amount ofcarboxylic acid 1 and amine 2. This reaction is conventionally conductedfor peptide synthesis and synthetic methods used therein can also beemployed to prepare compound 3 which is a compound of formula I above.For example, well known coupling reagents such as carbodiimides with orwithout the use of well known additives such as N-hydroxysuccinimide,1-hydroxybenzotriazole, etc. can be used to facilitate coupling. Thereaction is conventionally conducted in an inert aprotic polar diluentsuch as dimethylformamide, dichloromethane, chloroform, acetonitrile,tetrahydrofuran and the like. Alternatively, the acid halide of compound1 can be employed in reaction (1) and, when so employed, it is typicallyemployed in the presence of a suitable base to scavenge the acidgenerated during the reaction. Suitable bases include, by way ofexample, triethylamine, diisopropylethylamine, N-methylmorpholine andthe like.

Various compounds as described herein can be prepared by N-substitutionreactions of compound 2. Reaction of compound 2 with an carboxylic acidderivative can also lead to various compounds as described herein. Bothreactions are described below.

Synthesis of Carboxylic Acid Starting Materials

Carboxylic acids 1 can be prepared by several divergent synthetic routeswith the particular route selected relative to the ease of compoundpreparation, commercial availability of starting materials, whether n isone or two.

A. Synthesis of Carboxylic Acids

When n is one, a first synthetic method involves the introduction of theR¹ group to the amino acid NH₂CH(R²)COOH or ester thereof.

The introduction of the R¹ group onto the amino acid NH₂CH(R²)COOH orester thereof can be accomplished in several methods. For example,conventional coupling of a halo acetic acid with a primary amine formsan amino acid as shown in reaction (2) below:

wherein R¹and R² are as defined above and Z is a halo group such aschloro or bromo. Alternatively, leaving groups other than halo may beemployed such as triflate and the like. Additionally, suitable esters of4 may be employed in this reaction.

As above, reaction (2) involves coupling of a suitable haloacetic acidderivative 4 with a primary amine 5 under conditions that provide foramino acid 6. This reaction is described by, for example, Yates, etal.¹⁴ and proceeds by combining approximately stoichiometric equivalentsof haloacetic acid 4 with primary amine 5 in a suitable inert diluentsuch as, water, dimethylsulfoxide (DMSO) and the like. The reactionemploys an excess of a suitable base such as sodium bicarbonate, sodiumhydroxide, etc. to scavenge the acid generated by the reaction. Thereaction is preferably conducted at from about 25° C. to about 100° C.until reaction completion which typically occurs within 1 to about 24hours. This reaction is further described in U.S. Pat. No. 3,598,859,which is incorporated herein by reference in its entirety. Upon reactioncompletion, N-substituted amino acid 6 is recovered by conventionalmethods including precipitation, chromatography, filtration and thelike.

In reaction (2), each of the reagents (haloacetic acid 4, primary amine5 and alcohol 6) are well known in the art with a plurality of eachbeing commercially available.

In an alternative embodiment, the R¹ group can be coupled to an alanineester (or other suitable amino acid ester) by conventional N-arylation.For example, a stoichiometric equivalent or slight excess of the aminoacid ester can be dissolved in a suitable diluent such as DMSO andcoupled with a halo-R¹ compound, Z—R¹ where Z is a halo group such aschloro or bromo and R¹ is as defined above. The reaction is conducted inthe presence of an excess of base such as sodium hydroxide to scavengethe acid generated by the reaction. The reaction typically proceeds atfrom 15° C. to about 250° C. and is complete in about 1 to 24 hours.Upon reaction completion, N-substituted amino acid ester is recovered byconventional methods including chromatography, filtration and the like.This ester is then hydrolyzed by conventional methods to provide forcarboxylic acid 1 for use in reaction (1).

In still another alternative embodiment, the esterified amino acidsdescribed above can be prepared by reductive amination of a suitablepyruvate ester in the manner illustrated in reaction (3) below:

wherein R¹ is typically an alkyl group and R¹ and R² are as definedabove.

In reaction (3), approximately stoichiometric equivalents of pyruvateester 7 and amine 5 are combined in an inert diluent such as methanol,ethanol and the like and the reaction solution treated under conditionsthat provide for imine formation (not shown). The imine formed is thenreduced under conventional conditions by a suitable reducing agent suchas sodium cyanoborohydride, H₂/palladium on carbon and the like to formthe N-substituted amino acid ester 8. In a particularly preferredembodiment, the reducing agent is H₂/palladium on carbon which isincorporated into the initial reaction medium which permits iminereduction in situ in a one pot procedure to provide for theN-substituted amino acid ester 8.

The reaction is preferably conducted at from about 20° C. to about 80°C. at a pressure of from 1 to 10 atmospheres until the reaction iscomplete, which typically occurs within 1 to about 24 hours. Uponreaction completion, N-substituted amino acid ester 8 is recovered byconventional methods including chromatography, filtration and the like.

Subsequent hydrolysis of the ester 8 leads to the correspondingcarboxylic acid derivative 1 which can be employed in reaction (1)above.

For compounds where n is two, conventional coupling of a second aminoacid (e.g., NH₂CH(R²)C(O)OR where R is typically an alkyl group) to theamino acid produced above (i.e., R¹NHCH(R²)COOH) provides for esters ofan analogue of carboxylic acid 1 which are then conventionallyde-esterified to provide for an analogue of compound 1.

Alternatively, an ester such as H₂NCH(R²)C(O)NHCH(R²)COOR where each R²is independently as defined above and R is typically an alkyl group canfirst be formed by conventional peptide synthetic procedures,N-substitution can be conducted in the manner described above followedby de-esterification to provide for analogues of carboxylic acids 1where n is two.

When n is one, a first synthetic method involves conventional couplingof an carboxylic acid derivative with a primary amine of an esterifiedamino acid as shown in reaction (4) below:

wherein R is typically an alkyl group and R¹, R², X′ and X″ are asdefined above.

Reaction (4) merely involves coupling of a suitable carboxylic acidderivative 9 with the primary amine of amino acid ester 10 underconditions that provide for the N-acetyl derivative 11. Alternatively,the carboxylic acid R′COOH can be used in place of compound 9 to provideintermediates useful for preparing compounds of Formula VI above. Thisreaction is conventionally conducted for peptide synthesis and syntheticmethods used therein can also be employed to prepare the N-acetyl aminoacid esters 11 of this invention. For example, well known couplingreagents such as carbodiimides with or without the use of well knownadditives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. canbe used to facilitate coupling. The reaction is conventionally conductedin an inert aprotic polar diluent such as dimethylformamide,dichloromethane, chloroform, acetonitrile, or tetrahydrofuran.Alternatively, the acid halide of compound 9 can be employed in reaction(4) and, when so employed, it is typically employed in the presence of asuitable base to scavenge the acid generated during the reaction.Suitable bases include, by way of example, triethylamine,diisopropylethylamine, and N-methylmorpholine.

Reaction (4) is preferably conducted at from about 0° C. to about 60° C.until the reaction is complete, which typically occurs within 1 to about24 hours. Upon reaction completion, N-acetyl amino acid ester 11 isrecovered by conventional methods including precipitation,chromatography, and filtration or alternatively is hydrolyzed to thecorresponding acid without purification and/or isolation other thanconventional work-up (e.g., aqueous extraction, etc.).

In reaction (4), each of the reagents (carboxylic acid derivative 9 andamino acid ester 10) are well known in the art with a plurality of eachbeing commercially available.

When n is two, a further amino acid ester is coupled to the amino acidester 11 by first de-esterifying 11 and then using well known peptidecoupling chemistry with well known coupling reagents such ascarbodiimides with or without the use of well known additives such asN-hydroxysuccinimide and 1-hydroxybenzotriazole, which can be used tofacilitate coupling. The reaction is conventionally conducted in aninert aprotic polar diluent such as dimethylformamide, dichloromethane,chloroform, acetonitrile, or tetrahydrofuran. De-esterification of theresulting ester provides for carboxylic acids 1 having n equal to 2.

Alternatively, carboxylic acids 1 having n equal to 2 can be prepared byfirst forming the ester, N-acetylating these esters and thende-esterifying the resulting product.

Carboxylic acids 1 having n equal to 1 or 2 can also be prepared byusing polymer-supported forms of carbodiimide peptide coupling reagents.A polymer-supported form of EDC, for example, has been described(Tetrahedron Letters, 34(48), 7685 (1993))¹⁰. Additionally, a newcarbodiimide coupling reagent, PEPC, and its correspondingpolymer-supported forms have been discovered and are very useful forpreparing such compounds.

Polymers suitable for use in making a polymer-supported coupling reagentare either commercially available or may be prepared by methods wellknown to those of skill in the polymer arts. A suitable polymer mustpossess pendant sidechains bearing moieties reactive with the terminalamine of the carbodiimide. Such reactive moieties include chloro, bromo,iodo and methanesulfonyl. Preferably, the reactive moiety is achloromethyl group. Additionally, the polymer backbone must be inert toboth the carbodiimide and reaction conditions under which the ultimatepolymer-bound coupling reagents will be used.

Certain hydroxymethylated resins may be converted into chloromethylatedresins useful for the preparation of polymer-supported couplingreagents. Examples of these hydroxylated resins include the4-hydroxymethylphenylacetamidomethyl resin (Pam Resin) and4-benzyloxybenzyl alcohol resin (Wang Resin) available from AdvancedChemtech of Louisville, Ky., USA (see Advanced Chemtech 1993-1994catalog, page 115). The hydroxymethyl groups of these resins may beconverted into the desired chloromethyl groups by any of a number ofmethods well known to the skilled artisan.

Preferred resins are the chloromethylated styrene/divinylbenzene resinsbecause of their ready commercial availability. As the name suggests,these resins are already chloromethylated and require no chemicalmodification prior to use. These resins are commercially known asMerrifield's resins and are available from Aldrich Chemical Company ofMilwaukee, Wis., USA (see Aldrich 1994-1995 catalog, page 899). Methodsfor the preparation of PEPC and its polymer-supported forms are outlinedin the following scheme.

Such methods are described more fully in PCT Application PCT/US97/22986,which application is incorporated herein by reference in its entirety.Briefly, PEPC is prepared by first reacting ethyl isocyanate with1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with4-toluenesulfonyl chloride to provide PEPC. The polymer-supported formis prepared by reaction of PEPC with an appropriate resin under standardconditions to give the desired reagent.

The carboxylic acid coupling reactions employing these reagents areperformed at about ambient temperature to about 45° C., for from about 3to 120 hours. Typically, the product is isolated by washing the reactionmixture with CHCl₃ and concentrating the remaining organics underreduced pressure. As discussed supra, isolation of products fromreactions where a polymer bound reagent has been used is greatlysimplified, requiring only filtration of the reaction mixture and thenconcentration of the filtrate under reduced pressure.

Sulfonamidation Chemistry

Sulfonamides, such as those in Formula III, can be readily preparedusing known sulfonamidation reactions. These typically involve thereaction of sulfonyl chlorides with primary or secondary amines in thepresence of a tertiary amine or other suitable acid scavenger (See, forExample, page 923, Morrison and Boyd, Organic Chemistry, fourthedition).

Synthesis of Sulfonic Acid Starting Materials

Suitable sulfonic acids can be prepared by several divergent syntheticroutes with the particular route selected relative to the ease ofcompound preparation, and commercial availability of starting materials.

A. Synthesis of Sulfonic Acids

Alkyl sulfonic acids can be prepared using means well known to those ofskill in the art, as described, for example, in U.S. Pat. Nos. 2,493,038and 2,697,722, the contents of which are hereby incorporated byreference. One method for preparing alkyl sulfonic acids is by theoxidation of disulfides, which can themselves be prepared by theoxidation of thiols. Aromatic sulfonic acids can be produced by thesulfonating action of sulfuric acid, SO₃, oleum or alkyl sulfonic acidson aromatic compounds using techniques well known to those of skill inthe art.

Activation of Sulfonic Acids

Suitable sulfonic acid derivatives can be prepared, for example, byreacting a sulfonic acid with a chlorinating reagent such as phosphorouspentachloride or sulfonyl chloride.

Preparation of Ureas

Ureas can be prepared by any known methodology, but preferably areprepared by reacting an amine with an isocyanate, as described on page844 of Morrison and Boyd, Organic Chemistry, Fourth Edition, Allyn andBacon, ed., Boston (1983). Suitable isocyanates can be prepared usingmethods known to those of skill in the art.

Preparation of Cyclic Amino Compounds

Cyclic amino compounds 2 employed in reaction (1) above are generallyaminolactams, aminolactones, aminothiolactones and aminocycloalkylcompounds which can be represented by the formula:

wherein X is as defined above, Q is preferably selected from the groupconsisting of —O—, —S—, >NR⁶, and >CR⁷R⁸ where each of R⁶, R⁷ and R⁸ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, heteroaryl and heterocyclic with the proviso that if Q is—O—, —S— or >NR⁶, then X is oxo or dihydro, and W together with Q, C═Xand CH forms a lactone, thiolactone, lactam, cyclic ketone, cyclicalcohol, a heterocycle, and the like.

The aminolactams, aminolactones and aminothiolactones of the formulasabove can be prepared by use or adaptation of known chemical syntheseswhich syntheses are well described in the literature. See, e.g.,Ogliaruso and Wolfe, Synthesis of Lactones and Lactams, Patai, et al.Editor, J. Wiley & Sons, New York, N.Y., USA, pp. 1085 et seq. (1993)¹⁵.

Specifically, 3-amino substituted lactams 13 with 5, 6 or 7 ring atomsmay be prepared by the direct cyclization of a suitable α, omega-diaminoacid ester 12 as shown in reaction (5) below:

wherein L is a linking group (typically an alkylene group) of from 2-4atoms, Pr is a suitable protecting group such as t-butoxycarbonyl,carbobenzyloxy, or the like and R⁹ is an alkoxy or aryloxy group such asmethoxy, ethoxy, p-nitrophenoxy, N-succinimidoxy, and the like. Thereaction may be carried out in a solvent such as water, methanol,ethanol, pyridine, and the like. Such reactions are exemplified bycyclization of a lysine ester to a caprolactam as described by Ugi, etal., Tetrahedron, 52(35):11657-11664 (1996)¹⁶. Alternatively, such acyclization can also be conducted in the presence of dehydrating agentssuch as alumina or silica to form lactams as described by Blade-Font,Tetrahedron Lett., 21:2443 (1980)¹⁷.

The preparation of aminolactams alkylated on the amino group of thecyclic lactam is described by Freidinger, et al., J. Org. Chem.,47:104-109 (1982)¹⁸ and illustrated in reaction (6) below:

wherein L and R⁶ are as defined above.

In reaction (6), reductive amination of 14 with aldehyde 15 andsubsequent ring closure by methods using, for example, EDC provides foraminolactam 16. The preparation of 6 membered lactams using this generalprocedure is described by Semple, et al., J. Med. Chem., 39:4531-4536(1996)¹⁹.

The internal cyclization of an amide anion with a halide or equivalentthereof can sometimes be used to particular advantage in the synthesisof smaller ring lactams where the stereochemistry of the amino-lactamcenter is available from the standard amino-acid pool. This approach isillustrated in reaction (7) below:

where R⁶ is as defined above.

The approach of reaction (7) is presented by Semple, et al., supra.¹⁹,and Freidinger, et al., J. Org. Chem., 47:104-109 (1982)¹⁸ where adimethylsulfonium leaving group is generated from methyl iodidetreatment of an alkyl methyl sulfide 17 to provide for lactam 18. Asimilar approach using a Mitsunobu reaction on an omega alcohol is foundHolladay, et al., J. Org. Chem., 56:3900-3905 (1991)²⁰.

In another method, lactams 20 can be prepared from cyclic ketones 19using either the well known Beckmann rearrangement (e.g., Donaruma, etal., Organic Reactions, 11:1-156 (1960))²¹ or the well known Schmidtreaction (Wolff, Organic Reactions, 3:307-336 (1946))²² as shown inreaction (8) below:

wherein L is as defined above.

Application of these two reactions leads to a wide variety of lactamsespecially lactams having two hydrogen atoms on the carbon α to thelactam carbonyl which lactams form a preferred group of lactams in thesynthesis of the compounds described above. In these reactions, the Lgroup can be highly variable including, for example, alkylene,substituted alkylene and hetero containing alkylene with the provisothat a heteroatom is not adjacent to the carbonyl group of compound 19.Additionally, the Beckmann rearrangement can be applied to bicyclicketones as described in Krow, et al., J. Org. Chem., 61:5574-5580(1996)²³.

The preparation of lactones can be similarly conducted using peracids ina Baeyer-Villiger reaction on ketones. Alternatively, thiolactones canbe prepared by cyclization of an omega —SH group to a carboxylic acidand thiolactams can be prepared by conversion of the oxo group to thethiooxo group by P₂S₅ or by use of the commercially available Lawesson'sReagent, Tetrahedron, 35:2433 (1979)²⁴.

One recently reported route for lactam synthesis is a variation of theSchmidt reaction through the use of an alkylazide, eitherintermolecularly or intramolecularly, through a tethered alkylazidefunction that attacks a ketone under acidic conditions. Gracias, et al.,J. Am. Chem. Soc., 117:8047-8048 (1995)²⁵ describes the intermolecularversion whereas Milligan, et al., J. Am. Chem. Soc., 117:10449-10459(1995)²⁶ describes the intramolecular version. One example of theintramolecular version is illustrated in reaction (9) below:

where R¹⁰ is exemplified by alkyl, substituted alkyl, alkoxy,substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic.

In this reaction, ketone 21 is converted to an α-(w-alkyl)ketone 22which is cyclized to form bicyclic lactam 23. Such intramolecularreactions are useful in forming bicyclic lactams having 5-7 members andthe lactam ring of 6-13 members. The use of heteroatoms at non-reactivesites in these rings is feasible in preparing heterobicyclic lactams.

Still another recent approach to the synthesis of lactams is describedby Miller, et al., J. Am. Chem. Soc., 118:9606-9614 (1996)²⁷ andreferences cited and is illustrated in reaction (10) below:

where R⁶ and Pr are as defined above and R¹¹ is exemplified by halo,alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl,cycloalkyl and heterocyclic wherein the aryl, heteroaryl, cycloalkyl andheterocyclic group is optionally fused to the lactam ring structure.

Specifically, in reaction (10), lactam 26 is formed from an appropriateunsaturated amide (e.g., 24) through a ruthenium or molybdenum complexescatalyzed olefin metathesis reaction to form unsaturated lactam 25 whichcan be used herein without further modification. However, theunsaturation in 25 permits a myriad of techniques such as hydroboration,Sharpless or Jacobsen epoxidations, Sharpless dihydroxylations,Diels-Alder additions, dipolar cycloaddition reactions and many morechemistries to provide for a wide range of substituents on the lactamring. Moreover, subsequent transformations of the formed substitutionleads to other additional substituents (e.g., mesylation of an alcoholfollowed by nucleophilic substitution reactions). See, for example,March, et al. for a recitation of numerous such possible reactions.²⁸Saturated amides used in this reaction are conventional with amide 24being commercially available.

Related chemistry to cyclize amides to form lactams is disclosed byColombo, et al., Tetrahedron Lett., 35(23):4O31-4034 (1994)²⁹ and isillustrated in reaction (11) below:

In this reaction, proline derivative 27 is cyclized via atributyltin-radical cyclization to provide for lactam 28.

Some of the lactams described above contain the requisite amino group ato the lactam carbonyl whereas others did not. However, the introductionof the required amino group can be achieved by any of several routesdelineated below which merely catalogue several recent literaturereferences for this synthesis.

For example, in a first general synthetic procedure, azide or aminedisplacement of a leaving group a to the carbonyl group of the lactamleads to the α-aminolactams. Such general synthetic procedures areexemplified by the introduction of a halogen atom followed bydisplacement with phthalimide anion or azide and subsequent conversionto the amine typically by hydrogenation for the azide as described inRogriguez, et al., Tetrahedron, 52:7727-7736 (1996)³⁰, Parsons, et al.,Biochem. Biophys. Res. Comm., 117:108-113 (1983)³¹ and Watthey, et al.,J. Med. Chem., 28:1511-1516 (1985)³². One particular method involvesiodination and azide displacement on, for example, benzyllactams asdescribed by Armstrong, et al., Tetrahedron Lett., 35:3239 (1994)³³ andby King, et al., J. Org. Chem., 58:3384 (1993)³⁴.

Another example of this first general procedure for the synthesis ofα-aminolactams from the corresponding lactam involves displacement of atriflate group by an azido group as described by Hu, et al., TetrahedronLett., 36(21):3659-3662 (1995)³⁵.

Still another example of this first general procedure uses a Mitsunobureaction of an alcohol and a nitrogen equivalent (either —NH₂ or aphthalimido group) in the presence of an azodicarboxylate and atriarylphosphine as described in Wada, et al., Bull. Chem. Soc. Japan,46:2833-2835 (1973)³⁶ using an open chain reagent.

Yet another example of this first general procedure involves reaction ofα-chlorolactams with anilines or alkyl amines in a neat mixture at 120°C. to provide for 2-(N-aryl or N-alkyl)lactams as described by Gaetzi,Chem. Abs., 66:28690m.³⁷

In a second general synthetic procedure, reaction of an enolate with analkyl nitrite ester to prepare the a oxime followed by reduction yieldsthe α-aminolactam compound. This general synthetic procedure isexemplified by Wheeler, et al., Organic Syntheses, Coll. Vol. VI, p.840³⁸ which describes the reaction of isoamyl nitrite with a ketone toprepare the desired oxime. The reduction of the oxime methyl ester(prepared from the oxime by reaction with methyl iodide) is described inthe J. Med. Chem., 28(12):1886 (1985)³⁹ and the reduction of α-oximinocaprolactams by Raney-nickel and palladium catalysts is described byBrenner, et al., U.S. Pat. No. 2,938,029.⁴⁰

In a third general synthetic procedure, direct reaction of an enolatewith an electrophilic nitrogen transfer agent can be used. The originalreaction employed toluenesulfonyl azide but was improved as described byEvans, et al., J. Am. Chem. Soc., 112:4011-4030 (1990)⁴¹. Specifically,direct introduction of an azido group which can be reduced to the amineby hydrogenation is described by Micouin, et al., Tetrahedron,52:7719-7726 (1996)⁴². Likewise, the use of triisopropylbenzenesulfonylazide as the azide transferring agent for reaction with an enolate isdescribed by Evans, et al., supra. The use of triphenylphosphine toreduce the α-azidolactams to the corresponding aminolactams in thebenzodiazepine series is disclosed by Butcher, et al., TetrahedronLett., 37(37):6685-6688 (1996)⁴³. Lastly, diazo transfer of β-diketonesand subsequent reduction of the diazo group to the amino group isexemplified by Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995)³⁵who used Raney-nickel and hydrogen in acetic acid and acetic anhydrideas the solvent.

In a fourth general procedure, N-substituted lactams are first convertedto the 3-alkoxycarbonyl derivatives by reaction with a dialkyl carbonateand a base such as sodium hydride. See, for example, M. L. Reupple, etal., J. Am. Chem. Soc., 93:7021 et seq. (1971)⁴⁴ The resulting estersserve as starting materials for conversion to the 3-amino derivatives.This conversion is achieved via the Curtius reaction as shown inreaction (12) below:

where Pr is as defined above and R¹² is typically hydrogen, an alkyl oran aryl group.

The Curtius reaction is described by P. A. S. Smith, Organic Reactions,3:337-449 (1946).⁴⁵ Depending on the reaction conditions chosen, Pr=H ora protecting group such as Boc. For example, when R=H, treatment of theacid with diphenylphosphoryl azide in the presence of t-butanol providesthe product wherein Pr=Boc.

The α-aminolactams employed as the cyclic amino compounds 2 in reaction(1) above include ring N-substituted lactams in addition to ring N—Hlactams. Some methods for preparing ring N-substituted lactams have beendescribed above. More generally, however, the preparation of thesecompounds range from the direct introduction of the substituent afterlactam formation to essentially introduction before lactam formation.The former methods typically employ a base and an primary alkyl halidealthough it is contemplated that a secondary alkyl halide can also beemployed although yields may suffer.

Accordingly, a first general method for preparing N-substituted lactamsis achieved via reaction of the lactam with base and alkyl halide (oracrylates in some cases). This reaction is quite well known and basessuch as sodamide, sodium hydride, LDA, LiHMDS in appropriate solventssuch as THF, DMF, etc. are employed provided that the selected base iscompatible with the solvent. See for example: K. Orito, et al.,Tetrahedron, 36:1017-1021 (1980)⁴⁶ and J. E. Semple, et al., J. Med.Chem., 39:4531-4536 (1996)¹⁹ (use of LiHMDS with either R—X or acrylatesas electrophiles).

A second general method employs reductive amination on an amino functionthat is then cyclized to an appropriate ester or other carbonylfunction.

A third general method achieves production of the N-substitution duringlactam formation. Literature citations report such production fromeither photolytic or thermal rearrangement of oxaziridines, particularlyof N-aryl compounds. See, for example, Krimm, Chem. Ber., 91:1057(1958)⁴⁷ and Suda, et al., J. Chem. Soc. Chem Comm., 949-950, (1994).⁴⁸Also, the use of methyl hydroxylamine for the formation of nitrones andtheir rearrangement to the N-methyl derivatives is reported by Barton,et al., J. Chem. Soc., 1764-1767 (1975).⁴⁹ Additionally, the use of theoxaziridine process in chiral synthesis has been reported by Kitagawa,et al., J. Am. Chem. Soc., 117:5169-5178 (1975).⁵⁰

A more direct route to obtain N-phenyl substituted lactams from thecorresponding NH lactams through the use of t-butyltetramethylguanidineand triphenylbismuth dichloride is disclosed by Akhatar, et al., J. Org.Chem., 55:5222-5225 (1990)⁵¹ as shown in reaction (13) below.

Given that numerous methods are available to introduce an α-amino grouponto a lactam (or lactone) ring, the following lactams (and appropriatecorresponding lactones) are contemplated for use in the synthesis ofcompounds described above. Similar alcohol functions at the carbonylposition are derivative of either amine ring opening of cyclic epoxides,ring opening of aziridines, displacement of appropriate halides withamine or alcohol nucleophiles, or most likely reduction of appropriateketones. These ketones are also of interest to the present invention.

Monocyclic lactams as described by Nedenskov, et al., Acta Chem. Scand.,12:1405-1410 (1958)⁵² are represented by the formula:

where R₁ and R₂ are exemplified by alkyl, aryl or alkenyl (e.g., allyl).

Monocyclic lactams containing a second nitrogen ring atom as describedby Sakakida, et al., Bull. Chem. Soc. Japan, 44:478-480 (1971)⁵³ arerepresented by the formula:

where R is exemplified by CH₃— or PhCH₂—.

Monocyclic lactams having hydroxyl substitution on the ring as describedby Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995)³⁵ arerepresented by the formula:

where R is exemplified by benzyl (includes both the cis and transhydroxy lactams).

The direct preparation N-substituted lactams of 5-8 members from thecorresponding ketones is described by Hoffman, et al., Tet. Lett.,30:4207-4210 (1989). These lactams are represented by the formula:

wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, or benzyl.

N-Methoxylactams prepared from cyclohexanone and dimethoxyamine aredescribed by Vedejs, et al., Tet. Lett., 33:3261-3264 (1992).⁵⁵ Thesestructures are represented by the formula:

Substituted 3-aminoazetidinone derivatives prepared by a variety ofroutes including those described by van der Steen, et al., Tetrahedron,47, 7503-7524 (1991)⁵⁶, Hart, et al., Chem Rev., 89:1447-1465 (1989)⁵⁷and references cited therein are represented by the formula:

where R₁ and R₂ are independently selected from alkyl, substitutedalkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic orare fused to form a cyclic group.

Ring substituted lactams are described by Lowe, et al., Bioorg. Med.Chem. Lett., 4:2877-2882 (1994)⁵⁸ and are represented by the formula:

wherein R₂ and R₃ are exemplified by aryl and substituted aryl and R₁ isexemplified by alkyl or hydrogen.

The synthesis of substituted 3-aminopyrrolidones from α-bromoketones isdescribed by McKennis, Jr., et al., J. Org. Chem., 28:383-387 (1963)⁵⁹.These compounds are represented by the formula:

where R¹ is aryl or heteroaryl and R² corresponds to any substituent forwhich the corresponding amine R²—NH₂ exists.

Additional references for the synthesis of α aminolactams are asfollows:

1. Shirota, et al., J. Med. Chem., 1623-1627 (1977)⁶⁰ which describesthe synthesis of

2. Overberger, et al., J. Am. Chem. Soc., 85:3431 (1963)⁶¹ whichdescribes the preparation of optically active-methylcaprolactam of theformula:

3. Herschmann, Helv. Chim. Acta, 32:2537 (1949)⁶² describes thesynthesis of a disubstituted caprolactam from the Beckman rearrangementof menthone which is represented by the formula:

4. Overberger, et al., Macromolecules, 1:1 (1968)⁶³ describes thesynthesis of eight-membered lactams from 3-methylcycloheptanone as shownbelow:

5. The synthesis of benzolactams (benzazepinones) has been reported byBusacca, et al., Tet. Lett., 33:165-168 (1992)⁶⁴.

by Croisier, et al., U.S. Pat. No. 4,080,449⁶⁵:

and by J. A. Robl, et al., Tetrahedron Lett., 36(10):1593-1596 (1995)⁶⁶who employed an internal Friedel-Crafts like cyclization to prepare thetricyclic benzyllactams shown below where Pht is the phthalimidoprotecting group:

Another tricyclic lactam series is disclosed by Flynn, et al., J. Med.Chem., 36:2420-2423 (1993)⁶⁷ and references cited therein.

6. Orito, et al., Tetrahedron, 36:1017-1021 (1980)⁶⁸ discloses phenylsubstituted benzazepinones represented by the formula:

wherein R=H or CH₃—;

Kawase, et al., J. Org. Chem., 54:3394-3403 (1989)⁶⁹ discloses aN-methoxy benzazepinone represented by the formula:

7. Lowe, et al., J. Med. Chem., 37:3789-3811 (1994)⁷⁰ describes severalsynthetic pathways to substituted benzazepinones of the formula:

where R₁ is substituted aryl or cyclohexyl, X is a suitable substituentand R₂ can be H or alkyl. The syntheses described in Lowe are, however,adaptable to form numerous R¹ substituents.

8. Robl, et al., Bioorg. Med. Chem. Lett., 4:1789-1794 (1994)⁷¹ andreferences cited therein as well as Skiles, et al., Bioorg. Med. Chem.Lett., 3:773-778 (1993)⁷² disclose benzofused lactams which containadditional heteroatoms in the lactam ring. These compounds arerepresented by the formula:

where X is O and R₂=H or CH₃ or X=S and R₂=H. In either case, R₁=H oralkyl. Also, in Skiles, the thio group of the thiolactam can be oxidizedto the SO₂group. These structures are also presented from Beckmannrearrangement in Grunewald, et al., J. Med. Chem., 39(18):3539 (1996).⁷³

9. Also syntheses for the benzoheterolactam series is presented inThomas, et al., J. Chem. Soc., Perkin II, 747 (1986)⁷⁴ which could leadto compounds of the formula:

where X is O or H₂ and R¹ is CO₂R.

10. Further examples of benzazepinones are found in Warshawsky, et al.,Bioorg. Med. Chem. Lett., 6:957-962 (1996)⁷⁵ which discloses

The synthesis can be generalized to produce R=alkyl or aryl.

11. Ben-Ishai, et al., Tetrahedron, 43:439-450 (1987)⁷⁶ describessyntheses which could lead to several benzolactams of the formula

wherein n=0,1,2 and R=—CH₃, PhCH₂— and H.

12. van Niel et al., Bioorg. Med. Chem. Lett., 5:1421-1426 (1995)⁷⁷reports the synthesis of

wherein X is —OH, —NH₂ or —NR⁶R⁶ where R⁶ is as defined above. Thereported ketone is a versatile synthetic intermediate which can bemodified by conventional methods such as reductive amination, reduction,etc.

13. Kawase, et al., J. Org. Chem., 54:3394-3403 (1989)⁷⁸ describes asynthetic method for the preparation of:

In addition to the above, saturated bicyclic α-aminolactams are alsocontemplated for use in the synthesis of compounds of formulas I-VI.Such saturated bicyclic α-aminolactams are well known in the art. Forexample, Edwards, et al., Can. J. Chem., 49:1648-1658 (1971)⁷⁹ describesseveral syntheses of bicyclic lactams of the formula:

Similarly, Milligan, et al., J. Am. Chem. Soc., 117:10449-10459 (1995)⁸⁰and references cited therein report the synthesis of lactams of theformula:

wherein R1 and R2 are H or —CH₃, ring A can have from 6-13 members andring B can have from 5-7 members. R can be alkyl, aryl, cycloalkyl, andthe like.

The introduction of a heteroatom into the saturated cyclic structurefused to the lactam ring is disclosed by Curran et al., Tet. Lett.,36:191-194 (1995)⁸¹ who describe a synthetic method which can be used toobtain a lactam of the formula:

by Slusarchyk, et al., Bioorg. Med. Chem. Lett., 5:753-758 (1995)⁸² whodescribe syntheses which could lead to a lactam of the formula:

and by Wyvratt, et al., Eur. Pat. Appl. 61187 (1982)⁸³ who describe alactam of the formula:

Lactams having further heteroatom(s) in the cyclic lactam structure (inaddition to the nitrogen of the amido group of the lactam) are describedby Cornille, et al., J. Am. Chem. Soc., 117:909-917 (1995)⁸⁴ whodescribe lactams of the formula:

J. Kolc, Coll. Czech. Chem. Comm., 34:630 (1969)⁸⁵ who describes lysinessuitable for cyclization to lactams which have a hetero lactam ring atomas shown by the formula:

wherein X=O, S and NR where R is, for example, alkyl, substituted alkyl,aryl, heteroaryl, heterocyclic, heterocyclooxy, and the like.

Similarly, each of Dickerman, et al., J. Org. Chem., 14:530 (1949)⁸⁶,Dickerman, et al., J. Org. Chem., 20:206 (1955)⁸⁷, and Dickerman, etal., J. Org. Chem., 19:1855 (1954)⁸⁸ used the Schmidt and Beckmannreactions on substituted 4-piperidones to provide for lactams of theformula:

where R is acyl, alkyl, substituted alkyl, aryl, heteroaryl orheterocyclic provided that R is not an acid labile group such as t-Boc;and R′ is hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,heterocyclooxy, halo, cyano, nitro, trihalomethyl, and the like.

An internal cyclization of appropriate ethylenediamine amides onto aketone or aldehyde is described by Hoffman, et al., J. Org. Chem.,27:356-589 (1962)⁸⁹ as follows:

Ring expansion methodology based on β lactams to provide for larger ringlactams containing an aza group has twice been reported in Wasserman, etal., J. Am. Chem. Soc., 103:461-2 (1981)⁹⁰ and in Crombie, et al.,Tetrahedron Lett., 27(42):5151-5154 (1986).⁹¹

Dieckmann methodology has been used to prepare aza caprolactams fromunsymmetrical amines such as shown below by Yokoo, et al., Bull, Chem.Soc. Jap., 29:631 (1956).⁹²

wherein R is as defined in this reference. The disclosure of Yokoo, etal. can be extended to cover R being alkyl, substituted alkyl, aryl,alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic,heterocyclooxy, alkenyl, substituted alkenyl, and the like.

The synthesis of various members of the oxalactam series has beenreported by Burkholder, et al., Bioorg. Med. Chem. Lett., 2:231 (1993)⁹³and references cited therein which oxalactams are represented by theformula:

wherein R′ is as defined in the reference and R can be alkyl,substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl,cycloalkyl, heterocyclic, heterocyclooxy, alkenyl, substituted alkenyl,and the like.

The synthesis of thialactams (generally oxalactams can be made by thesame methodology) has been reported by Freidinger, et al., J. Org.Chem., 47:104-109 (1982)¹⁸ who prepared thialactams of the formula:

This reference provides a series of procedures having broad applicationfor synthesis of lactams, permitting R in the above formula to bederived from any amine (alkyl, aryl, heteroaryl, etc.) with therestriction being that the R-group does not contain any functionalgroups reactive with formaldehyde (e.g., primary and secondary amines).The general synthetic scheme provided by Freidlinger, et al. is:

The coupling agent is any standard reagent used in the formation oftypical peptide or amide bonds, for example, carbodiimide reagents. See,also, Karanewsky, U.S. Pat. No. 4,460,579 and Kametani, et al.,Heterocycles, 9:831-840 (1978).⁹⁵

The Friedinger procedure can be extended to afford disubstitutedthialactams of the following structure:

In practical terms, R₂ will be limited to aryl and heteroaryl groups andsterically hindered alkyl groups such as t-butyl. R₁ can be highlyvariable and is limited only by subsequent reaction steps.

Still further is the Kametani procedure which provides for lactams asfollows:

In principle, the Kametani procedure allows for a wide selection of R1and R2 groups limited primarily by stability to the reaction conditions.

See, for example, Yanganasawa, et al., J. Med. Chem., 30: 1984-1991(1987)⁹⁶ and J. Das et al., Biorg. Med. Chem. Lett., 4:2193-2198(1994)⁹⁷ which describes general methods for the synthesis of isomeric7-membered thialactams of the following structure:

The first synthetic route is:

R₂ can be highly variable (e.g., alkyl, substituted alkyl, aryl,heteroaryl, heterocyclic and the like) since a number of well documentedroutes exist for the synthesis of nitroethylene derivatives fromaldehydes and nitromethane (Henry reaction) followed by dehydration. R₁is limited to groups that can undergo alkylation reactions.

The second compound series can be prepared as follows:

In this synthesis, R₂ can be highly variable. The starting componentrequired to introduce R₂ can be readily derived by the reduction of anyknown α-BOC-amino acid to the alcohol derivative followed by formationof the mesylate.

As noted above, the primary approaches to the preparation of lactams isthe Beckmann/Schmidt ring expansion reaction using either inter- orintramolecular approaches serves to prepare lactams of various ringsizes. The intramolecular approach generates bicyclic materials with thelactam nitrogen incorporated into the ring fusion. Additional approachesset forth above involve the internal cyclization of omega-aminoacids/esters where the construction of the substituent pattern takesplace prior to cyclization, and internal cyclization of an electrophiliccenter onto a nucleophilic functional group as in the Friedel Craftstype cyclization used in the Ben-Ishal procedure for makingbenzazepinones. This latter procedure is applicable to a wide variety ofheteroaromatics as well as benzenoid rings, and may also be applied tonon-aromatic double or triple bonds to generate a wide array ofsubstituents or ring fusions.

Deoxygenation of the lactam by reagents such as diborane, LiAlH₄, andthe like leads to azaheterocycles (═X is dihydro).

Similarly, for X═H, OH, such compounds can be prepared by epoxidation ofcycloalkenyl groups followed by oxirane opening by, e.g., ammonia. Afterformation of compounds of Formulas I-VI, ═X being H, OH can be oxidizedto provide for cycloalkylones (═X being oxo).

Additionally, the 5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivativesemployed in this invention can be prepared using conventional proceduresand reagents. For example, an appropriately substitutedN-tert-Boc-2-amino-2′-methylbiphenyl compound can be cyclized to formthe corresponding 5,7-dihydro-6H-dibenz[b,d]azepin-6-one derivative byfirst treating the biphenyl compound with about 2.1 to about 2.5equivalents of a strong base, such as sec-butyl lithium. This reactionis typically conducted at a temperature ranging from about −80° C. toabout −60° C. in an inert diluent such as THF. The resulting dianion isthen treated with dry carbon dioxide at a temperature of about −78° C.to afford the 5,7-dihydro-6H-diben[b,d]azepin-6-one. This procedure isdescribed further in R. D. Clark et al., Tetrahedron, 49(7), 1351-1356(1993) and references cited therein.

After forming the 5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the amidenitrogen can be readily alkylated by first treating the dibenazepinonewith about 1.1 to about 1.5 equivalents of a strong base, such as sodiumhydride, in an inert diluent, such as DMF. This reaction is typicallyconducted at a temperature ranging from about −10° C. to about 80° C.for about 0.5 to about 6 hours. The resulting anion is then contactedwith an excess, preferably about 1.1 to about 3.0 equivalents, of analkyl halide, typically an alkyl chloride, bromide or iodide. Generally,this reaction is conducted at a temperature of about 0° C. to about 100°C. for about 1 to about 48 hours.

An amino group can then be introduced at the 5-position of the7-alkyl-5,7-dihydro-6H-diben[b,d]azepin-6-one using conventionalprocedures and reagents. For example, treatment of7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one with an excess of butylnitrite in the presence of a strong base, such as potassium1,1,1,3,3,3-hexamethyldisilazane (KHMDS), affords5-oximo-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Subsequentreduction of the oximo group by hydrogenation in the presence of acatalyst, such as palladium on carbon, then provides5-amino-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Otherconventional amination procedures, such as azide transfer followed byreduction of the azido group, may also be employed.

Similarly, various benzodiazepine derivatives suitable for use in thisinvention can be prepared using conventional procedures and reagents.For example, a 2-aminobenzophenone can be readily coupled toα-(isopropylthio)-N-(benzyloxycarbonyl)glycine by first forming the acidchloride of the glycine derivative with oxalyl chloride, and thencoupling the acid chloride with the 2-aminobenzophenone in the presenceof a base, such as 4-methylmorpholine, to afford the2-[-(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]-aminobenzophenone.Treatment of this compound with ammonia gas in the presence of anexcess, preferably about 1.1 to about 1.5 equivalents, of mercury (II)chloride then affords the2-[N-(α-amino)-N-(benzyloxycarbonyl)-glycinyl]aminobenzophenone. Thisintermediate can then be readily cyclized by treatment with glacialacetic acid and ammonium acetate to provide the3-(benzyloxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one 1.Subsequent removal of the Cbz group affords the3-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one.

Alternatively, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-ones can bereadily aminated at the 3-position using conventional azide transferreactions followed by reduction of the resulting azido group to form thecorresponding amino group. The conditions for these and relatedreactions are described in the examples set forth below. Additionally,2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-ones are readily alkylatedat the 1-position using conventional procedures and reagents. Forexample, this reaction is typically conducted by first treating thebenzodiazepinone with about 1.1 to about 1.5 equivalents of a base, suchas sodium hydride, potassium tert-butoxide, potassium1,1,1,3,3,3-hexamethyldisilazane, cesium carbonate, in an inert diluent,such as DMF. This reaction is typically conducted at a temperatureranging from about −78° C. to about 80° C. for about 0.5 to about 6hours. The resulting anion is then contacted with an excess, preferablyabout 1.1 to about 3.0 equivalents, of an alkyl halide, typically analkyl chloride, bromide or iodide. Generally, this reaction is conductedat a temperature of about 0° C. to about 100° C. for about 1 to about 48hours.

Additionally, the3-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines employed inthis invention are typically prepared by first coupling malonic acidwith a 1,2-phenylenediamine. Conditions for this reaction are well knownin the art and are described, for example, in PCT Application WO96-US8400 960603. Subsequent alkylation and amination using conventionalprocedures and reagents affords various3-amino-1,5-bis(alkyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines.Such procedures are described in further detail in the example set forthbelow.

Accordingly, a vast number of lactams, lactones and thiolactones areavailable by art recognized procedures. Similarly, the art is repletewith examples of aminocycloalkyl compounds for use in the synthesis ofcompounds of Formulas I-VI above.

In the synthesis of the compounds described herein using the syntheticmethods described above, the starting materials can contain a chiralcenter (e.g., alanine) and, when a racemic starting material isemployed, the resulting product is a mixture of R,S enantiomers.Alternatively, a chiral isomer of the starting material can be employedand, if the reaction protocol employed does not racemize this startingmaterial, a chiral product is obtained. Such reaction protocols caninvolve inversion of the chiral center during synthesis.

Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds described herein areusually administered in the form of pharmaceutical compositions. Thesecompounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal. These compounds are effective as both injectable and oralcompositions. Such compositions are prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.

The pharmaceutical compositions contain, as the active ingredient, oneor more of the compounds described above, associated withpharmaceutically acceptable carriers. The pharmaceutical compositionscan be prepared, for example, by mixing the active ingredient with anexcipient, diluting the active ingredient with an excipient, orenclosing the active ingredient within a carrier such as a capsule(including microparticles, nanoparticles, and liposomes), sachet, paperor other container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 5 to about 100 mg, more usually about 10 toabout 30 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient. Preferably, the compound of Formulas I-VI above is employedat no more than about 20 weight percent of the pharmaceuticalcomposition, more preferably no more than about 15 weight percent, withthe balance being pharmaceutically inert carrier(s).

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, and the severity ofthe patient's symptoms.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can separated by enteric layer whichserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

The liquid forms in which the compositions may be incorporated foradministration orally or by injection include aqueous solutions,suitably flavored syrups, aqueous or oil suspensions, and flavoredemulsions with edible oils such as cottonseed oil, sesame oil, coconutoil, or peanut oil, as well as elixirs and similar pharmaceuticalvehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The following formulation examples illustrate the pharmaceuticalcompositions of the present invention.

FORMULATION EXAMPLE 1

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

FORMULATION EXAMPLE 2

A tablet formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

FORMULATION EXAMPLE 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

FORMULATION EXAMPLE 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity (mg/ Ingredient tablet) Active Ingredient 30.0 mg Starch 45.0mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as10% solution in sterile water) Sodium carboxymethyl starch 4.5 mgMagnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinyl-pyrrolidone is mixed with the resultant powders, which arethen passed through a 16 mesh U.S. sieve. The granules so produced aredried at 50 to 60° C. and passed through a 16 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 30 mesh U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yield tabletseach weighing 150 mg.

FORMULATION EXAMPLE 5

Capsules, each containing 40 mg of medicament are made as follows:

Quantity (mg/ Ingredient capsule) Active Ingredient 40.0 mg Starch 109.0mg Magnesium stearate 1.0 mg Total 150.0 mg

The active ingredient, starch, and magnesium stearate are blended,passed through a No. 20 mesh U.S. sieve, and filled into hard gelatincapsules in 150 mg quantities.

FORMULATION EXAMPLE 6

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient 25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7

Suspensions, each containing 50 mg of medicament per 5.0 ml dose aremade as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mgSucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 ml

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

FORMULATION EXAMPLE 8

Quantity (mg/ Ingredient capsule) Active Ingredient 15.0 mg Starch 407.0mg Magnesium stearate 3.0 mg Total 425.0 mg

The active ingredient, starch, and magnesium stearate are blended,passed through a No. 20 mesh U.S. sieve, and filled into hard gelatincapsules in 560 mg quantities.

FORMULATION EXAMPLE 9

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 1.0 mg corn oil   1 ml

(Depending on the solubility of the active ingredient in corn oil, up toabout 5.0 mg or more of the active ingredient may be employed in thisformulation, if desired).

FORMULATION EXAMPLE 10

A topical formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g LiquidParaffin 20 g White Soft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system used for the transport ofbiological factors to specific anatomical regions of the body isdescribed in U.S. Pat. No. 5,011,472 which is herein incorporated byreference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs. Latentiationis generally achieved through blocking of the hydroxy, carbonyl,sulfate, and primary amine groups present on the drug to render the drugmore lipid soluble and amenable to transportation across the blood-brainbarrier. Alternatively, the delivery of hydrophilic drugs may beenhanced by intra-arterial infusion of hypertonic solutions which cantransiently open the blood-brain barrier.

Other suitable formulations for use in the present invention can befound in Remington's Pharmaceutical Sciences, Mace Publishing Company,Philadelphia, Pa., 17th ed. (1985).

Utility

The compounds and pharmaceutical compositions of the invention areuseful in inhibiting β-amyloid peptide release and/or its synthesis,and, accordingly, have utility in diagnosing and treating Alzheimer'sdisease in mammals including humans.

As noted above, the compounds described herein are suitable for use in avariety of drug delivery systems described above. Additionally, in orderto enhance the in vivo serum half-life of the administered compound, thecompounds may be encapsulated, introduced into the lumen of liposomes,prepared as a colloid, or other conventional techniques may be employedwhich provide an extended serum half-life of the compounds. A variety ofmethods are available for preparing liposomes, as described in, e.g.,Szoka, et al., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,837,028, thecontents of each of which is incorporated herein by reference.

The amount of compound administered to the patient will vary dependingupon what is being administered, the purpose of the administration, suchas prophylaxis or therapy, the state of the patient, the manner ofadministration, and the like. In therapeutic applications, compositionsare administered to a patient already suffering from AD in an amountsufficient to at least partially arrest further onset of the symptoms ofthe disease and its complications. An amount adequate to accomplish thisis defined as “therapeutically effective dose.” Amounts effective forthis use will depend on the judgment of the attending cliniciandepending upon factors such as the degree or severity of AD in thepatient, the age, weight and general condition of the patient, and thelike. Preferably, for use as therapeutics, the compounds describedherein are administered at dosages ranging from about 1 to about 500mg/kg/day.

In prophylactic applications, compositions are administered to a patientat risk of developing AD (determined for example by genetic screening orfamilial trait) in an amount sufficient to inhibit the onset of symptomsof the disease. An amount adequate to accomplish this is defined as a“prophylactically effective dose.” Amounts effective for this use willdepend on the judgment of the attending clinician depending upon factorssuch as the age, weight and general condition of the patient, and thelike. Preferably, for use as prophylactics, the compounds describedherein are administered at dosages ranging from about 1 to about 500mg/kg/day.

As noted above, the compounds administered to a patient are in the formof pharmaceutical compositions described above. These compositions maybe sterilized by conventional sterilization techniques, or may besterile filtered. The resulting aqueous solutions may be packaged foruse as is, or lyophilized, the lyophilized preparation being combinedwith a sterile aqueous carrier prior to administration. The pH of thecompound preparations typically will be between 3 and 11, morepreferably from 5 to 9 and most preferably from 7 and 8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of pharmaceutical salts.

The compounds described herein are also suitable for use in theadministration of the compounds to a cell for diagnostic and drugdiscovery purposes. Specifically, the compounds may be used in thediagnosis of cells releasing and/or synthesizing β-amyloid peptide. Inaddition the compounds described herein are useful for the measurementand evaluation of the activity of other candidate drugs on theinhibition of the cellular release and/or synthesis of β-amyloidpeptide.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

BEMP = 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine Boc = t-butoxycarbonyl BOP =benzotriazol-1-yloxy-tris (dimethylamino) phosphoniumhexafluorophosphate bd = broad doublet bs = broad singlet d = doublet dd= doublet of doublets DIC = diisopropylcarbodiimide DMF =dimethylformamide DMAP = dimethylaminopyridine DMSO = dimethylsulfoxideEDC = ethyl-1-(3-dimethyaminopropyl)carbodiimide eq. = equivalents EtOAc= ethyl acetate g = grams HOBT = 1-hydroxybenzotriazole hydrate Hunig'sbase = diisopropylethylamine L = liter m = multiplet M = molar max =maximum meq = milliequivalent mg = milligram mL = milliliter mm =millimeter mmol = millimole MOC = methoxyoxycarbonyl N = normal N/A =not available ng = nanogram nm = nanometers OD = optical density PEPC =1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide PP-HOBT =piperidine-piperidine-1-hydroxybenzotrizole psi = pounds per square inch= phenyl q = quartet quint. = quintet rpm = rotations per minute s =singlet t = triplet TFA = trifluoroacetic acid THF = tetrahydrofuran tlc= thin layer chromatography L = microliter UV = ultra-violet

In the examples below, all temperatures are in degrees Celcius (unlessotherwise indicated). The compounds set forth in the examples below wereprepared using the following general procedures as indicated.

The term “Aldrich” indicates that the compound or reagent used in theprocedure is commercially available from Aldrich Chemical Company, Inc.,1001 West Saint Paul Avenue, Milwaukee, Wis. 53233 USA.

The term “Fluka” indicates that the-compound or reagent is commerciallyavailable from Fluka Chemical Corp., 980 South 2nd Street, RonkonkomaN.Y. 11779 USA.

The term “Lancaster” indicates that the compound or reagent iscommercially available from Lancaster Synthesis, Inc., P.O. Box 100Windham, N.H. 03087 USA.

The term “Sigma” indicates that the compound or reagent is commerciallyavailable from Sigma, P.O. Box 14508, St. Louis Mo. 63178 USA;

The term “Chemservice” indicates that the compound or reagent iscommercially available from Chemservice, Inc., Westchester, Pa.

The term “Bachem” indicates that the compound or reagent is commerciallyavailable from Bachem Biosciences Inc., 3700 Horizon Drive, Renaissanceat Gulph Mills, King of Prussia, Pa. 19406 USA.

The term “Maybridge” indicates that the compound or reagent iscommercially available from Maybridge Chemical Co. Trevillett, Tintagel,Cornwall PL34 OHW United Kingdom.

The term “TCI” indicates that the compound or reagent is commerciallyavailable from TCI America, 9211 North Harborgate Street, Portland Oreg.97203.

The term “Alfa” indicates that the compound or reagent is commerciallyavailable from Johnson Matthey Catalog Company, Inc. 30 Bond Street,Ward Hill, Mass. 01835-0747.

The term “Novabiochem” indicates that the compound or reagent iscommercially available from Calbiochem-Novabiochem Corp. 10933 NorthTorrey Pines Road, P.O. Box 12087, La Jolla Calif. 92039-2087.

The term “Oakwood” indicates that the compound or reagent iscommercially available from Oakwood, Columbia, S.C.

The term “Advanced Chemtech” indicates that the compound or reagent iscommercially available from Advanced Chemtech, Louisville, Ky.

The term “Pfaltz & Bauer” indicates that the compound or reagent iscommercially available from Pfaltz & Bauer, Waterbury, Conn., USA.

I. COUPLING PROCEDURES General Procedure A First EDC Coupling Procedure

To a 1:1 mixture of the corresponding carboxylic acid and thecorresponding amino acid ester or amide in CH₂Cl₂ at 0° C. was added 1.5equivalents triethylamine, followed by 2.0 equivalentshydroxybenzotriazole monohydrate and then 1.25 equivalents ofethyl-3-(3-dimethylamino)propyl carbodiimide HCl. The reaction mixturewas stirred overnight at room temperature and then transferred to aseparatory funnel. The mixture was washed with water, saturated aqueousNaHCO₃, 1N HCl and saturated aqueous NaCl, and then dried over MgSO₄.The resulting solution was stripped free of solvent on a rotaryevaporator to yield the crude product.

General Procedure B Second EDC Coupling Procedure

A mixture of the corresponding acid (1 eqv), N-1-hydroxybenzotriazole(1.6 eqv), the corresponding amine (1 eqv), N-methylmorpholine (3 eqv)and dichloromethane (or DMF for insoluble substrates) was cooled in anice-water bath and stirred until a clear solution was obtained. EDC (1.3eqv) was then added to the reaction mixture. The cooling bath was thenallowed to warm to ambient temperature over 1-2 h and the reactionmixture was stirred overnight. The reaction mixture was then evaporatedto dryness under vacuum. To the residue was added 20% aqueous potassiumcarbonate and the mixture was shaken throughly and then allowed to standuntil the oily product solidified (overnight if necessary). The solidproduct was then collected by filtration, washed thoroughly with 20%aqueous potassium carbonate, water, 10% HCl, and water to give theproduct, usually in pure state. No racemization was observed.

General Procedure C Third EDC Coupling Procedure

The carboxylic acid was dissolved in methylene chloride. Thecorresponding amino acid ester or amide (1 eq.), N-methylmorpholine (5eq.) and hydroxybenzotriazole monohydrate (1.2 eq.) were added insequence. A cooling bath was applied to the round bottomed flask untilthe solution reached 0° C. At that time, 1.2 eq. of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added.The solution was allowed to stir overnight and come to room temperatureunder nitrogen pressure. The reaction mixture was worked up by washingthe organic phase with saturated aqueous sodium carbonate, 0.1M citricacid, and brine before drying with sodium sulfate. The solvents werethen removed to yield crude product.

General Procedure D Fourth EDC Coupling Procedure

A round bottom flask was charged with the corresponding carboxylic acid(1.0 eq.), hydroxybenzotriazole hydrate (1.1 eq.) and the correspondingamine (1.0 eq.) in THF under nitrogen atmosphere. An appropriate amount(1.1 eq for free amines and 2.2 eq. for hydrochloride amine salts) ofbase, such as Hunig's base was added to the well stirred mixturefollowed by EDC (1.1 eq.). After stirring from 4 to 17 hours at roomtemperature the solvent was removed at reduced pressure, the residuetaken up in ethyl acetate (or similar solvent) and water, washed withsaturated aqueous sodium bicarbonate solution, 1 N HCl, brine, driedover anhydrous sodium sulfate and the solvent removed at reducedpressure to provide the product.

General Procedure E BOP Coupling Procedure

To a stirred solution of N-(3,5-difluorophenylacetyl)alanine (2 mmol) inDMF, cooled in an ice-water bath, was added BOP (2.4 mmol) andN-methylmorpholine (6 mmol). The reaction mixture was stirred for 50min. and then a solution of α-amino-α-lactam (2 mmol) in DMF cooled at0° C. was added. The cooling bath was allowed to warm to ambienttemperature over 1-2 h and the reaction mixture was then stirredovernight. A 20% aqueous potassium carbonate solution (60 mL) was addedand this mixture shaken throughly. No solid formed. The mixture was thenwashed with ethyl acetate (150 mL) and evaporated to dryness undervacuum to give a white solid. Water (50 mL) was then added and thismixture was shaken throughly. The precipitate that formed was collectedby filtration, then washed thoroughly with water, followed by 1 mL ofdiethyl ether to give the product (51 mg, 0.16 mmol, 7.8%).

General Procedure F Coupling of an Acid Chloride with an Amino AcidEster

To a stirred solution of (D,L)-alanine isobutyl ester hydrochloride (4.6mmol) in 5 ml of pyridine was added 4.6 mmol of the acid chloride.Precipitation occurred immediately. The mixture was stirred for 3.5 h,dissolved in 100 mL of diethyl ether, washed with 10% HCl three times,brine once, 20% potassium carbonate once and brine once. The solutionwas dried over magnesium sulfate, filtered, and evaporated to yield theproduct. Other amino acid esters may also be employed in this procedure.

General Procedure G Coupling of a Carboxylic Acid with an Amino AcidEster

A solution of the carboxylic acid (3.3 mmol) and 1,1′-carbodiimidazole(CDI) in 20 mL THF was stirred for 2 h. (D,L)-alanine isobutyl esterhydrochloride (3.6 mmol) was added, followed by 1.5 mL (10.8 mmol) oftriethylamine. The reaction mixture was stirred overnight. The reactionmixture was dissolved in 100 mL of diethyl ether, washed with 10% HClthree times, brine once, 20% potassium carbonate once and brine once.The solution was dried over magnesium sulfate, filtered, and evaporatedto yield the product. Other amino acid esters may also be employed inthis procedure.

General Procedure H Fifth EDC Coupling Procedure

In a round bottom flask was added a carboxylic acid (1.1 eq.) in THF, anamine hydrochloride (1.0 eq.), 1-hydroxybenzotriazole hydrate (1.1 eq.),N,N-diisopropylethylamine (2.1 eq.), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.1eq.). The reaction mixture stirred at room temperature for 10-20 hoursunder an atmosphere of nitrogen. The mixture was diluted with EtOAc andwashed with 0.1 M HCl (1×10 mL), saturated NaHCO₃ (1×10 mL), H₂O (1×10mL), and brine and dried over MgSO₄. The drying agent was removed byfiltration and the filtrate was concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel followed bytrituration from EtOAc and hexanes.

General Procedure I Sixth EDC Coupling Procedure

To a solution or suspension of the amine or amine hydrochloride (1.0eq.) in THF (0.05-0.1 M) under N₂ at 0° C. was added the carboxylic acid(1.0-1.1 eq.), hydroxybenzotriazole monohydrate (1.1-1.15 eq.), Hunig'sbase (1.1 eq. for free amines and 1.1-2.3 eq. for hydrochloride aminesalts), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.1-1.15 eq.). The cooling bath was removed and themixture allowed to warm to room temperature for 10-24 hours. Thesolution or mixture was diluted with EtOAc, in a 3-5 volume multiple ofthe initial THF volume, and washed with 0.1-1.0 M aq. HCl (1 or 2×),dilute NaHCO₃ (1 or 2×), and brine (1×). Then, the organic phase wasdried over either MgSO₄ or Na₂SO₄, filtered, concentrated to provide thecrude product, which was either further purified or utilized withoutfurther purification.

General Procedure J EEDQ Coupling Procedure

To a solution of the amine in THF (1.0 eq., 0.05-0.08 M, final molarity)under N₂ at room temperature was added the N-t-Boc protected amino acid(1.1 eq., either as a solid or in THF via cannula), followed by EEDQ(Aldrich, 1.1 eq.). The pale yellow solution was stirred at roomtemperature for 16-16.5 hours, then diluted with EtOAc (in a 3-5 volumemultiple of the initial THF volume), and washed with 1M aq. HCl (2×),dilute aq. NaHCO₃ (2×), and brine (1×). The organic phase was dried overeither Na₂SO₄ or MgSO₄, filtered, and concentrated.

II. CARBOXYLIC ACIDS General Procedure II-A

Ester Hydrolysis to Free Acid

Ester hydrolysis to the free acid was conducted by conventional methods.Below are two examples of such conventional de-esterification methods.

Method A: To a carboxylic ester compound in a 1:1 mixture of CH₃OH/H₂Owas added 2-5 equivalents of K₂CO₃. The mixture was heated to 50° C. for0.5 to 1.5 hours until tlc showed complete reaction. The reaction wascooled to room temperature and the methanol was removed on a rotaryevaporator. The pH of the remaining aqueous solution was adjusted to ˜2,and ethyl acetate was added to extract the product. The organic phasewas then washed with saturated aqueous NaCl and dried over MgSO₄. Thesolution was stripped free of solvent on a rotary evaporator to yieldthe product.

Method B: The amino acid ester was dissolved in dioxane/water (4:1) towhich was added LiOH (˜2 eq.) that was dissolved in water such that thetotal solvent after addition was about 2:1 dioxane:water. The reactionmixture was stirred until reaction completion and the dioxane wasremoved under reduced pressure. The residue was dissolved in water andwashed with ether. The layers were separated and the aqueous layer wasacidified to pH 2. The aqueous layer was extracted with ethyl acetate.The ethyl acetate extracts were dried over Na₂SO₄ and the solvent wasremoved under reduced pressure after filtration. The residue waspurified by conventional methods (e.g., recrystallization).

General Procedure II-B Acid Chloride Preparation

A carboxylic acid is dissolved in dichloromethane and this solution iscooled to 0° C. DMF (0.5 mL, catalytic) is added, followed by thedropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minuteperiod. The reaction is stirred for 3 h and then rotoevaporated atreduced pressure to give an oil which is placed on a high vacuum pumpfor 1 h to afford the acid chlorides.

General Procedure II-C Schotten-Baumann Procedure

The acid chloride (from General Procedure II-B) is added dropwise to a0° C. solution of L-alanine (Aldrich) (16.7 g, 0.187 mol) in 2 N sodiumhydroxide (215 mL, 0.43 mol) or another amino acid such as tert-leucineor phenyl glycine. The reaction is stirred for 1 h at 0° C. and thenovernight at room temperature. The reaction is diluted with water (100mL), then extracted with ethyl acetate (3×150 mL). The organic layer isthen washed with brine (200 mL), dried over MgSO₄, and rotoevaporated atreduced pressure to a residue. Recrystallization of the residue fromethyl acetate/hexanes affords the desired product in high yield.

General Procedure II-D Reductive Amination

To a solution of an arylamine in ethanol in a hydrogenation flask isadded 1 equivalent of a 2-oxocarboxylic acid ester (e.g., pyruvateester), followed by 10% palladium on carbon (25 weight percent based onthe arylamine). The reaction mixture is hydrogenated at 20 psi H₂ on aParr shaker until complete reaction is indicated by tlc (30 minutes to16 hours). The reaction mixture is then filtered through a pad of Celite545 (available from Aldrich Chemical Company, Inc.) and stripped free ofsolvent on a rotary evaporator. The crude product residue can then befurther purified via chromatography.

3. Cyclic Ketone Derivatives

General Procedure 3-A Jones Oxidation Procedure

The compound to be oxidized is stirred in acetone and the Jones reagentis added in portions until the starting material is consumed. Thereaction mixture is quenched with isopropanol and the mixture isfiltered through Celite and concentrated under reduced pressure. Theresidue is partitioned between ethyl acetate and water and the organicportion is dried over sodium sulfate and then concentrated under reducedpressure. The crude product is purified by silica gel chromatographyand/or recrystallization.

General Procedure 3-B Swern Oxidation Procedure

To a stirred mixture of oxalyl chloride (0.1.5 mL, 1.2 mmol) in 10 mL ofdichloromethane cooled to −78° C. is added DMSO (0.106 mL, 1.5 mmol) andthe mixture is stirred for 10 minutes. A solution of the alcohol (0.1828g, 0.60 mmol) in 20 mL of chloroform is added dropwise. The reactionmixture is stirred at −78° C. for 2 hours, and then 0.5 mL (3.6 mmol) oftriethylamine is added. Stirring is continued for 1 hour and then themixture is allowed to warm to room temperature and stirring is continuedat ambient temperature overnight. The mixture is then diluted with 50 mLof dichloromethane, washed with brine (3×), dried over magnesiumsulfate, filtered and evaporated to dryness to give a crude product thatis typically purified by column chromatography.

5. Lactams

General Procedure 5-A N-Alkylation of Lactams

To a stirred solution of a BOC-protected α-aminocaprolactam (6.87 g, 30mmol) in DMF (150 mL) was added in portions 97% NaH (1.08 g, 45 mmol).Bubbling occurred immediately and followed by heavy precipitation. After10 min., benzyl bromide (3.93 mL, 33 mmol) was added. The precipitatedissolved quickly and in about 10 min. a clear solution was obtained.The reaction mixture was stirred overnight and then evaporated ascompletely as possible on a rotovap at 30° C. Ethyl acetate (100 mL) wasadded to the residue and this mixture was washed with water, brine, anddried over magnesium sulfate. After filtration and concentration, athick liquid (10 g) was obtained which was then chromatographed oversilica gel with 1:3 ethyl acetate/hexane as the eluant to provide 5.51 g(58%) of the N-benzylated product as an oil. Other lactams andalkylating agents may be used in this procedure to obtain a wide varietyof N-alkylated lactams. Various bases, such as LiN(SiMe₃), may also beemployed.

General Procedure 5-B BOC Removal Procedure

The BOC-protected compound in a 1:1-2:1 mixture of CH₂Cl₂ andtrifluoroacetic acid was stirred until tlc indicated completeconversion, typically 2 hours. The solution was then stripped to drynessand the residue was taken up in ethyl acetate or CH₂Cl₂. The solutionwas washed with saturated aqueous NaHCO₃ and the aqueous phase wasadjusted to a basic pH, then extracted with ethyl acetate or CH₂Cl₂. Theorganic phase was washed with saturated aqueous NaCl and dried overMgSO₄. The solution was stripped free of solvent on a rotary evaporatorto yield the product.

General Procedure 5-C Synthesis of A-Aminolactams

The Schmidt reaction was conducted on 4-ethylcyclohexanone usinghydroxyamine sulfonic acid as described in Olah, Org. Synth. Collective,Vol. VII, page 254, to provide 5-ethylcaprolactam in 76% yield. Usingthe procedure described in Watthey, et al., J. Med. Chem., 1985, 28,1511-1516 , this lactam was then dichlorinated with PCl₅ at the αposition and reduced by hydrogenation to provide four isomericmonochlorides (two racemic mixtures). The two racemic mixtures wereseparated from each other by column chromatography using silica gel andeach racemic mixture was reacted with sodium azide to yield thecorresponding azide, which was hydrogenated to provide the correspondingα-aminolactams. Other cycloalkanones may be employed in this procedureto provide a wide variety of α-aminolactams. In some cases, such as whenpreparing the 9-membered ring α-aminolactam, longer reaction times,higher reaction temperatures and an excess of sodium azide may berequired. For example, the 9-membered ring α-aminolactam required 5equivalents of sodium azide, a reaction temperature of 120° C. and areaction time of 4 days. Such conditions can be readily determined bythose of ordinary skill in the art.

General Procedure 5-D Synthesis of4-Amino-1,2,3,4-tetrahydroisoquinoline-3-ones

The 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivatives employed inthis invention can be prepared by the following art-recognizedprocedures. The conditions for these reactions are further described inD. Ben-Ishai, et al., Tetrahedron, 43, 439450 (1987). The followingintermediates were prepared via this procedure:

3-amino-1,2,3,4-tetrahydroisoquinolin-3-one

4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

cis and trans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-3-one

4-amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one

9-amino(fluoren-1-yl)glycined-lactam-1,2,3,4-tetrahydroisoquinolin-3-one.

Step A—Preparation of N-Bismethoxycarbonylaminoacetic Acid: To one moleequivalent of glyoxylic acid in 2 liters of ethanol-free chloroform wasadded two mole equivalents of methyl carbamate and 0.1 mole equivalentof naphthalene sulfonic acid. The reaction mixture was then brought to areflux for 6 hours. Water was removed using an inverse Dean Stark trap.The reaction was then cooled and the product filtered and washed withchloroform. The white solid was recrystallized from ethylacetate/hexanes to give a white powder in 65% yield.

Step B—Coupling Procedure: To 0.0291 moles ofN-bismethoxycarbonylaminoacetic acid (or the appropriate carbocyclicacid) in 200 mL of THF was added one mole equivalent of EDCCHCl, abenzylamine, HOBT, and diisopropylethylamine. The reaction was allowedto stir at room temperature for 18 hours and then poured into aseparatory funnel and extracted into ethyl acetate. The ethyl acetatesolution was washed with 1 molar K₂CO₃ and then 1 molar HCl. The organiclayer was dried over Na₂SO₄, filtered and solvent removed to give thecrystalline benzylamide of N-bismethoxycarbonylaminoacetic acid. Thismaterial was used without further purification. Typical yields rangefrom 40-55%.

Step C—Cyclization Procedure: The benzylamide ofN-bismethoxycarbonylaminoacetic acid (0.008 moles) was dissolved in 75mL of methanesulfonic acid and allowed to stir over night at roomtemperature. The reaction mixture was poured over ice and extracted intoethyl acetate. The ethyl acetate extract was washed with 1 molar K₂CO₃and then 1 N HCl. The organic layer was dried over Na₂SO₄, filtered andthe solvent removed to give the crystalline4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one in 50-90%yield. This material was used without further purification.

Step D—Removal of the Methoxyoxycarbonyl Group (MOC): To the4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles)in 30 ML of acetonitrile was added 2 mole equivalents oftrimethylsilyliodide (TMSI). The reaction mixture was heated to 50-80°C. for 3 hrs and then cooled and poured into a separatory funnel. Thereaction mixture was diluted with ethyl acetate and washed with 1 molarK₂CO₃ and then with 5% NaHSO₃. The organic layer was dried over Na₂SO₄and filtered. The solvent was removed under reduced pressure to give the4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yieldsrange from 50-87%.

Step E—Alternative Procedure for Removal of the MethoxyoxycarbonylGroup: To 3.8 mmoles of the MOC-protected compound was added 10 mL of30% HBr in acetic acid and this reaction mixture was heated to 60° C.for 3 hrs. The mixture was then cooled and hexanes were added. Thehexanes layer was decanted off and the residue as placed under reducedpressure to give a tan solid. This solid was slurried in ether andfiltered to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-onehydrobromide salt. Typical yields range from 57-88%.

Example 5-A Synthesis of 3-Amino-1,2,3,4-tetrahydroquinolin-2-one

Step A: Sodium (0.30 g, 110M %) was added to anhydrous ethanol (45 mL)and the reaction mixture was stirred until homogenous. DiethylN-acetylaminomalonate (2.51 g, 100 M %) was added in one portion andthis mixture was stirred for 1 h. 2-Nitrobenzyl bromide (2.5 g, 100M %)was then added in one portion and the reaction mixture was stirred for 3h. The reaction was poured into water and extracted with ethyl acetate(3×) and then backwashed with water (3×) and brine (1×). Treatment withMgSO₄, rotoevaporation, and chromatography (30% EtOAc/hexanes) yieldeddiethyl N-acetylamino-2-nitrobenzylmalonate in 82% yield.

Step B: Diethyl N-acetylamino-2-nitrobenzylmalonate (1 g, 100M %) wasdissolved in a minimum amount of EtOH. Pd/C (10%, 0.05 g) was added andthe reaction mixture was subjected to 50 psi of H₂ for 3 hours. Thereaction was then filtered thru a pad of celite. Additional EtOH (25 mL)and TsOH (catalytic amount, 0.01 g) were added and this mixture wasrefluxed for 2 hours. The reaction was rotoevaporated to a residue andthen partitioned between water and ethyl acetate. The water layer wasextracted with ethyl acetate (3×) and the combined ethyl acetateextracts were washed with water (3×) and then brine (1×). Treatment withMgSO₄ and rotoevaporation yielded pure3-(N-acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (89%yield).

Step C: 3-(N-Acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one(0.75 g, 100M %) was suspended in 6N HCl (25 mL) and the mixture washeated to 100° C. for 3 hours. The reaction was cooled, rotoevaporatedto a residue and then partitioned between water and ethyl acetate. Thewater was extracted with ethyl acetate (3×) and the combined ethylacetate extracts were then washed with water (3×) and then brine (1×).Treatment with MgSO₄ followed by rotoevaporation yielded3-(R,S)-amino-1,2,3,4-tetrahydroquinolin-2-one (72% yield).

Example 5-B Synthesis of4-Amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: To a solution of 4-cyanopyridine (Aldrich) (0.150 moles) in 300mL of dry ether was added 1.1 eq. of phenylmagnesium bromide (Aldrich)dropwise. The reaction was refluxed for 2 hours and then stirredovernight at room temperature. Sodium borohydride (1.0 eq.) was addeddropwise as a solution in 200 mL of methanol (CAUTION—very exothermic).The reaction was then heated to reflux for 6 hours, cooled and quenchedwith a saturated solution of ammonium chloride. The solution wasdecanted from the salt in the reaction mixture and acidified with 1NHCl. After washing the aqueous layer with ethyl acetate, the pH ofaqueous layer was adjusted to about 9.0 with 1N sodium hydroxide (cold).The aqueous layer was then extracted with ethyl acetate and the organicextracts washed with brine, dried over Na₂SO₄, filtered and concentratedto give 4-pyridyl-a-benzyl amine as a thick yellow oil.

Step B: Following General Procedure 5-D and using 4-pyridyl-a-benzylamine, the title compound was prepared.

Example 5-C Synthesis of4-Amino-1-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: 2-Pyridyl-a-benzyl amine was prepared by substituting2-cyanopyridine (Aldrich) for 4-cyanopyridine in the procedure describedin Example 5-B.

Step B: Following General Procedure 5-D and using 4-pyridyl-a-benzylamine, the title compound was prepared.

Example 5-D Synthesis of4-Amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: Following the procedure described in J. Med. Chem., 1982, 25,1248, and using 3-benzoyl-pyridine (Aldrich), 3-pyridyl-a-benzyl aminewas prepared.

Step B: Following General Procedure 5-D and using 3-pyridyl-a-benzylamine, the title compound was prepared.

Example 5-E Synthesis of4-Amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: To a Parr bottle containing 3-benzoylbenzoic acid (0.044 moles)(Aldrich) in 150 mL of ethyl acetate and 4.5 mL of concentrated H₂SO₄was added 10 grams of 5% Pd/C. The mixture was hydrogenated on a Parrapparatus under hydrogen (45 psi) overnight. The reaction mixture wasthen filtered through Hyflo, washing with ethyl acetate. The filtratewas dried over Na₂SO₄, filtered and concentrated to give an oil. The oilwas slurried in hexane and the resulting white solid was collected byfiltration to afford 3-benzylbenzoic acid, which was used withoutfurther purification.

Step B: To the product from Step A (0.0119 moles) was added 150 mL ofCH₂Cl₂, one drop of DMF, 10 mL of oxalyl chloride, and the mixture wasstirred at room temperature for 3 hours. After cooling to 10° C., 30 mLof NH₄OH (exothermic) was added and the mixture was stirred for 30 min.The reaction mixture was then concentrated and the resulting residuediluted with ethyl acetate. The organic layer was washed with 1N NaOH,brine, dried over Na₂SO₄, and concentrated to give the3-(benzyl)benzamide as a white solid, which was used without furtherpurification.

Step C: To a solution of 3-(benzyl)benzamide (0.0094 moles) from Step Bin 70 of toluene was added 8 mL of Red-A17 (65+wt. % solution of sodiumbis(2-methoxyethoxy)aluminum hydride in toluene, Aldrich)(CAUTION—reaction very exothermic). The reaction mixture was then heatedat 60° C. for 2 hours and then poured over ice. The resulting mixturewas extracted with ethyl acetate and the combined extracts were washedwith water and brine. The organic layer was extracted with 1N HCl andthe aqueous layer washed with ethyl acetate. The pH of the aqueous layerwas then adjusted to about 9.0 with 1N NaOH and extracted with ethylacetate. The organic extracts were washed with water and brine and thenconcentrated to give 3-(benzyl)benzyl amine.

Step D: Following General Procedure 5-D and using 3-(benzyl)benzylamine, the title compound was prepared.

Example 5-F Synthesis of4-Amino-6-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: To a solution of 4-biphenylcarboxamide (Aldrich) (0.025 mole) in150 mL of THF cooled to 10° C. was added a solution of 1.5 eq of LAH (1Min THF) dropwise. The reaction mixture turned from a white slurry to agreen homogenous solution and then to a yellow homogeneous solution. Thereaction was then quenched with 2.5 mL of 1N NaOH. The mixture was thenfiltered through Hyflo and extracted with ethyl acetate. The organiclayer was then washed with 1N HCl. The pH of the resulting aqueous layerwas adjusted to about 9 with 1N NaOH and extracted with ethyl acetate.The organic extracts were washed with water and brine, and then driedover Na₂SO₄, filtered and concentrated to give 4-(phenyl)benzyl amine asa white solid.

Step B: Following General Procedure 5-D and using 4-(phenyl)benzylamine, the title compound was prepared.

Example 5-G Synthesis of cis- andtrans-4-Amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: Following General Procedure 5-D and using a-phenylbenzylamine(Aldrich), 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one wasprepared.

Step B: To a solution of4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one (0.00158 moles)from Step A in 20 mL of CH₂Cl₂ was added 2.0 eq. of triethylamine andBoc anhydride (1.1 eq.). The reaction was stirred overnight at roomtemperature and then concentrated. The residue was diluted with ethylacetate and water. The pH of the aqueous layer was adjusted to 3.0 withsodium bisulfate and the layers were separated. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby LC 2000, eluting with ethyl acetate/hexanes (70:30) to give a whitesolid containing a 1:1 mixture of cis- andtrans4-(N-Boc-amino)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-oneisomers. This mixture was recrystallized from ethyl acetate to give thepure trans isomer and a cis isomer-enriched mixture of cis and transisomers. This mixture was recrystallized again from ethylacetate/hexanes (70:30) to give the pure cis isomer.

Step C: The cis isomer and the trans isomer from Step B were separatelydeprotected using General Procedure 8-J to givecis4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one andtrans4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one.

Example 5-H Synthesis of4-Amino-7-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: To a solution of 1-bromo-3-phenylbenzene (Aldrich) (0.0858moles) in 300 mL of dry THF cooled to −78° C. was added tert-butyllithium (2 eq.) (1.7M in hexane) dropwise. The reaction mixture wasstirred for 40 min. at −78° C. and then quenched with 2 eq. of DMF(13.24 mL). The resulting mixture was stirred for 20 min. and thenpoured into a separatory funnel and extracted with CH₂Cl₂. The organicextracts were washed with water, dried over Na₂SO₄, filtered andconcentrated to give a brown oil. This oil was purified by LC 2000chromatography, eluting with ethyl acetate/hexanes (5:95) to give3-biphenylcarboxaldehyde.

Step B: To a solution of 3-biphenylcarboxaldehyde (0.011 eq.) in 30 mLof methanol was added 10 eq. of 7N NH₃/MeOH and NaCNBH₄ (2 eq.). Ayellow gum precipitated from solution. The solution was then heated at60° C. until gum dissolved and the solution was stirred at roomtemperature overnight. The reaction mixture was then concentrated andthe resulting residue diluted with ice water and ethyl acetate. Theorganic layer was then washed with brine and extracted with 5N HCl. ThepH of the aqueous layer was then adjusted to 12 and the aqueous layerwas extracted with cold ethyl acetate. The organic layer was dried overNa₂SO₄, filtered and concentrated to give 3-(phenyl)benzyl amine as anoil.

Step C: Following General Procedure 5-D and using 3-(phenyl)benzylamine, the title compound was prepared.

Example 5-I Synthesis of4-Amino-1-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

Step A: To a solution of benzoyl chloride (0.123 moles) (Aldrich) in 600mL of CH₂Cl₂ was added 2.0 eq. of phenethylamine (Aldrich) dropwise. Thereaction mixture was stirred at room temperature for 3 hours and thenpoured into a separatory and extracted with CH₂Cl₂. The organic extractswere washed with water and 1N HCl, and then dried over Na₂SO₄, filteredand concentrated to give N-phenethyl benzamide.

Step B: Reduction of N-phenethyl benzamide using the procedure ofExample 5-E, Step C afforded N-benzyl-N-phenethylamine as an oil.

Step C: Following General Procedure 5-D and usingN-benzyl-N-phenethylamine, the title compound was prepared.

Example 5-J Synthesis of 3-Amino-1-methyl-2-indolinone Monohydrochloride

Step A: (2,3-Dihydro-1-methyl-2-oxo-1H-indol-3-yl)carbamic acid methylester (CAS No. 110599-56-9) was prepared using the procedure describedin Ben-Ishai, D.; Sataty, I.; Peled, N.; Goldshare, R. Tetrahedron 1987,43, 439-450. The starting materials for this preparation wereN-methylaniline (CAS #100-61-8, Eastman Kodak Co.), glyoxylic acid (CAS#298-12-4, Aldrich), and methyl carbamate (CAS #598-55-0, Aldrich).

Step B: The product from Step A (333.5 mg) in 31% HBr in AcOH (10 mL)was heated to 50-60° C. for 2 hours. The resulting orange solution wasconcentrated to a thick orange oil which was dissolved in EtOAc (15 mL)and the product extracted into 1 M aq. HCl (10 mL). The aqueous acid wasneutralized with aq. NaHCO₃ and the product extracted into CH₂Cl₂ (10×10mL). HCl (gas) was passed through the combined CH₂Cl₂ extracts to form apurple solution. The solution was concentrated to provide the titlecompound (262.8 mg) as a purple solid.

Example 5-K Synthesis of3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril/Tin Complex

Step A:—Synthesis of 4-Phenyl-3,4-dihydrocarbostyril

4-Phenyl-3,4-dihydrocarbostyril (CAS #4888-33-9) was prepared in twosteps using the procedure described by Conley, R. T.; Knopka, W. N. J.Org. Chem. 1964, 29, 496-497. The starting materials for thispreparation were cinnamoyl chloride (Aldrich) and aniline (Aldrich). Thetitle compound was purified by flash chromatography eluting withCH₂Cl₂/EtOAc (4:1).

Step B:—Synthesis of 1-Methyl-4-phenyl-3,4-dihydrocarbostyril

To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineraloil) in THF (50 mL) under N₂ at 0° C. was added the product from Step A(1.0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5 minutes.The resulting pale yellow mixture was stirred at 0° C. for 10 minutes,then MeI (2.0 eq., 1.39 mL) was added. The opaque yellow mixture wasallowed to slowly (ice bath not removed) warm to ambient temperaturewith stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc (250 mL) wereadded and the phases partitioned. The organic phase was washed withdilute NaHCO₃ (1×100 mL), brine (1×100 mL), then dried over MgSO₄,filtered, concentrated, and the residue purified by flash chromatographyeluting with CH₂Cl₂/EtOAc (19:1 gradient to 15:1) to provide1-methyl-4-phenyl-3,4-dihydrocarbostyril.

Step C:—Synthesis of3-Azido-1-methyl-4phenyl-3,4-trans-dihydrocarbostyril

Following General Procedure 8-K,3-azido-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril was prepared as awhite solid. The product was purified by flash chromatography elutingwith CH₂Cl₂/hexanes/EtOAc 15:15:1.

Selected ¹H-NMR data for the title compound (CDCl₃): d=4.46 (d, 1H,J=10.57 Hz), 4.18 (d, 1H, J=10.63 Hz).

Step D:—Synthesis of3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril/Tin Complex

To a mixture of SnCl₂ (350.7 mg) in MeOH (7 mL) under N₂ at 0° C. wasadded the product from Step C (257.4 mg) in MeOH/THF (5 mL/5 mL) viacannula over a period of 1 minute. The cooling bath was removed thesolution allowed to warm to ambient temperature for 8 hours (No startingmaterial by TLC). The solution was concentrated to a yellow foam, THF(10 mL) was added and the mixture was reconcentrated and used withoutfurther purification.

Example 5-L Synthesis of3-Amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril

Step A:—Synthesis of3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril

3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril was preparedfollowing General Procedure 8-F using3-azido-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril from Example 5-K,Step C. The product was purified by L.C. 2000 eluting with EtOAc/hexanes(4:1) to yield a white solid.

Selected ¹H-NMR data for the title compound (CDCl₃): d=4.03 (d, 1H,J=12.8 Hz), 3.92 (d, 1H, J=12.7 Hz).

Step B:—Synthesis of3-(4-Chlorobenzylimine)-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril

To a solution of the product from Step A (1 eq., 239.6 mg) in CH₂Cl₂ (10mL) under N₂ at ambient temperature was added 4-chlorobenzaldehyde (1.05eq., 140 mg, Aldrich), Et₃N (1.4 eq., 185 mL), and MgSO₄ (3.6 eq., 411mg). The resultant mixture was stirred at room temperature for 73 hours.The solids were removed by filtration through a plug of Celite, rinsingwith CH₂Cl₂, and the filtrate concentrated to provide3-(4-chlorobenzylimine)-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyrilas a thick white foam.

Step C:—Synthesis of3-Amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril

To a solution of diisopropylamine (1.05 eq., 0.132 mL) in THF (5 mL)under N₂ at −78° C. was added a solution of n-BuLi (1.05 eq., 0.588 mlof a. 1.6 M solution in hexanes) and the result solution was stirred for30 minutes. To this solution was added the product from Step B (1.0 eq.,336 mg) in THF (2 mL) via cannula. The solution was allowed to warm to0° C., then quenched with 1 M aq. HCl (3 mL) and allowed to warm to roomtemperature with stirring overnight. The product was extracted into H₂Oand washed with EtOAc (1×), then the aqueous acid was basified with 1 Maq. K₂CO₃ and the product extracted into EtOAc. The EtOAc extract wasdried over Na₂SO₄, filtered, and concentrated to give3-amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril.

Selected ¹H-NMR data for the title compound (CDCl₃): d=4.31 (d, 1H,J=6.6 Hz).

Example 5-M Synthesis of3-Amino-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbostyril/TinComplex

Step A:—Synthesis of1-tert-Butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyril

1-tert-Butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyril was prepared fromthe product of Example 5-K, Step A (CAS #4888-33-9) by the Boc procedurefor aryl amides described by Grehn, L.; Gunnarsson, K.; Ragnarsson, U.Acta Chemica Scandinavica B 1986, 40, 745-750; employing (Boc)₂O(Aldrich) and catalytic DMAP (Aldrich) in acetonitrile. The product waspurified by flash chromatography eluting with CH₂Cl₂ gradient toCH₂Cl₂/EtOAc (19:1) and isolated as a pale yellow oil.

Step B—Synthesis of3-Azido-1-tert-butoxycarbonyl-4-phenyl-3,4-tans-dihydrocarbostyril

Following General Procedure 8-K using the product from Step A, the titlecompound was prepared as a 12.4:1 mixture of trans/cis isomers whichwere separated by flash chromatography eluting with hexanes/Et₂O (6:1gradient to 4:1) in the first column and hexanes/EtOAc (12:1) in asecond column. The pure trans isomer was used in Step C.

Selected ¹H-NMR data for the title compound (CDCl₃): d=4.45 (d, 1H,J=11.1 Hz), 4.24 (d, 1H, J=11.2 Hz).

Step C:—Synthesis of3-Amino-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbostyril/TinComplex

To a mixture of SnCl₂ (450.6 mg) in MeOH (9 mL) under N₂ at 0° C. wasadded the product from Part D (433.0 mg) in MeOH (15 mL) via cannulaover a period of 1 minute. The cooling bath was removed the solutionallowed to warm to ambient temperature for 17 hours. The solution wasconcentrated to an amorphous yellow solid and used without furtherpurification.

Example 5-N Synthesis of (S)-3-Amino-1-benzyl-d-valerolactam

Step A:—Synthesis of L-(+)-Ornithine Methyl Ester Hydrochloride

Into a stirred suspension of L-(+)-ornithine hydrochloride (Aldrich) inmethanol was bubbled anhydrous hydrochloric acid gas until the solutionwas saturated. The reaction mixture was capped with a rubber septum andstirring was continued overnight at room temperature. The solvent wasthen stripped under reduced pressure and the residue triturated withether. The resulting solid was dried under reduced pressure to affordL-(+)-ornithine methyl ester hydrochloride as a white solid (97% yield).

Step B:—Synthesis of (S)-3-Amino-d-valerolactam

Sodium spheres in oil (2.0 eq.) (Aldrich) were washed with hexanes (2×)and methanol (2.3 mL/mmol) was slowly added. The reaction mixture wasstirred under nitrogen until the sodium dissolved and thenL-(+)-ornithine methyl ester hydrochloride (1 eq.) in methanol (2.3mL/mmol) was added dropwise. The reaction mixture was stirred for 16hours and then diluted with diethyl ether (5 mL/mmol) and filtered toremove the solids. The solvent was then removed under reduced pressureand the residue was heated at 70° C. for 3 hours under reduced pressure.The residue was then triturated with dichloromethane/ether, the solventdecanted and the resulting residue dried under reduced pressure toafford (S)-3-amino-d-valerolactam (44% yield).

Step C:—Synthesis of N-Boc-(S)-3-Amino-d-valerolactam

(S)-3-Amino-d-valerolactam (1 eq.) was dissolved in dioxane and thesolution was chilled to 0° C. BOC-anhydride (1.3 eq.) was added and theice bath was removed allowing the solution to come to room temperatureand stirring was continued for 16 hours. The solution was rotaryevaporated to afford N-Boc-(S)-3-amino-d-valerolactam.

Step D:—Synthesis of (S)-3-Amino-1-benzyl-d-valerolactam

Following General Procedure 5-A and usingN-Boc-(S)-3-amino-d-valerolactam and benzyl bromide providedN-Boc-(S)-3-amino-1-benzyl-d-valerolactam. Removal of the Boc groupusing General Procedure 5-B afford the title compound.

Example 5-O Synthesis of4-Amino-2-aza-2-benzyl-3-oxo-bicyclo[3,2,1]octane Hydrochloride

Step A:—Synthesis of 2-aza-3-oxo-Bicyclo[3,2,1]octane and3-aza-2-oxo-Bicyclo[3,2,1]octane (9:1 Mixture)

To (″)-norcamphor (Aldrich) in 1 mL/mmole of acetic acid was added 1.5eq. of hydroxylamine-O-sulfonic acid. The reaction mixture was heated toreflux under nitrogen for 1 hour and then saturated sodium carbonate anddilute sodium hydroxide were added. The resulting mixture was extractedwith dichloromethane and the organic extracts washed with brine, driedover sodium sulfate, and the solvent removed under reduced pressure.Purification of the residue by column chromatography afforded a 9:1mixture of 2-aza-3-oxo-bicyclo[3,2,1]octane and3-aza-2-oxo-bicyclo[3,2,1]octane.

Step B:—Synthesis of 2-aza-2-Benzyl-3-oxo-bicyclo[3,2,1]octane FollowingGeneral Procedure 5-A and using the product for Step A and benzylbromide, 2-aza-2-benzyl-3-oxo-bicyclo[3,2,1]octane was prepared.

Step C:—Synthesis of 2-aza-2-Benzyl-4-oximino-3-oxo-bicyclo[3,2,1]octane

To a solution of 2-aza-2-benzyl-3-oxo-bicyclo[3,2,1]octane in THF wasadded 2.5 eq. of 1M t-BuOK/THF (Aldrich) and the resulting mixture wasstirred for 30 minutes. Isoamyl nitrite (1.5 eq.) was then addeddropwise and the reaction mixture was stirred overnight. To the reactionmixture was added 3N HCl and this mixture was extracted with ethylacetate and the organic extracts washed with water, dried, andconcentrated under reduced pressure. The residue was triturated withether/hexanes, the solvents decanted and the residue dried under reducedpressure to afford 2-aza-2-benzyl-4-oximino-3-oxo-bicyclo[3,2,1]octaneas a tan liquid (41% yield). This procedure is further described in Y.Kim, Tetrahedron Lett. 30(21), 2833-2636 (1989).

Step D:—Synthesis of 2-aza-2-Benzyl-4-amino-3-oxo-bicyclo[3,2,1]octane

A solution of 2-aza-2-benzyl-4-oximino-3-oxo-bicyclo[3,2,1]octane in 10mL/mmole of ethanol and 5.8 mL/mmole of 3N HCl containing 0.5 g/mmole of10% Pd/C was saturated with hydrogen gas to 45 psi. The mixture wasshaken for 3 hours and then filtered through a layer of Celite. Thefiltrate was dried over sodium sulfate and concentrated under reducedpressure to afford the title compound as a solid (86% yield). Thisprocedure is further described in E. Reimann, Arch. Pharm. 310, 102-109(1977).

6. Benzazepinone Derivatives and Related Compounds

General Procedure 6-A Alkylation of1-Amino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

Step A: 1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onewas prepared according to the procedure of Ben-Ishai et al.,Tetrahedron, 1987, 43, 430.

Step B: 1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one(2.0 g, 100 M %) was dissolved in DMF (30 mL) and NaH (95%, 0.17 g, 100M%) was added in one portion. The reaction mixture was stirred for 1 hourand then the appropriate alkyl iodide (300M %) was added and the mixturewas stirred for 12 hours. The reaction was poured into water andextracted with ethyl acetate (3×). The ethyl acetate extracts were thenwashed with water (3×) and brine (1×). Treatment with MgSO₄,rotoevaporation, and chromatography (30% EtOAc/hexanes) yielded1-ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onein 87% yield.

Step C:1-Ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one(1.0 g, 100M %) was suspended in 30 mL of 30% HBr/HOAc and heated to100° C. The reaction mixture was stirred for 5 hours at this temperatureand then the reaction was cooled and rotoevaporated to yield1-amino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one as thehydrobromide salt (100% yield).

General Procedure 6-B Alkylation of3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

Step A: 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was preparedfrom α-tetralone using the methods described in Armstrong et al.Tetrahedron Letters, 1994, 35, 3239. The following compounds were asprepared by this procedure for use in the following steps:

5-methyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from4-methyl-α-tetralone (Aldrich)); and

5,5-dimethyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from4,4-dimethyl-α-tetralone (Aldrich)).

Step B: 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (4.43 g, 100M%) was suspended in t-butanol (30 mL) and BOC-anhydride (7.5 mL, 130M %)was added dropwise. The reaction mixture was stirred for 2 hours andthen it was rotoevaporated to a residue which was chromatographed with60% ethyl acetate/hexanes to yield BOC-protected3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 87% yield.

Step C: BOC-protected 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(1.5 g, 100M %) was dissolved in DMF (20 mL) and NaH (95%, 0.13 g, 100M%) was added in one portion. The reaction mixture was stirred for 1 hourand then the appropriate alkyl iodide (300M %) was added and stirringwas continued for 12 hours. The reaction was poured into water andextracted with ethyl acetate (3×). The ethyl acetate extracts werewashed with water (3×) and then brine (1×). Treatment with MgSO₄,rotoevaporation, and chromatography (30% EtOAc/hexanes) yielded aBOC-protected 3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-onein 80% yield.

Step D: The BOC-protected3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (1.0 g, 100M %)was suspended in 30 mL of 1:1 CH₂Cl₂/triflouroacetic acid and themixture was stirred for 4 hours. The reaction was then rotoevaporated toyield the 3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100%yield).

Example 6-A Synthesis of3-Amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

Step A: 3-Amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one wasprepared from 4-methyl-α-tetralone using the methods described inArmstrong et al. Tetrahedron Letters, 1994, 35, 3239.

Step B: 3-Amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (9.3 g100M %) was dissolved in dioxane (300 mL) and the solution was chilledto 0° C. BOC-anhydride (13.89 g 130M %) was added and the ice bath wasremoved allowing the solution to come to room temperature and stirringwas continued for. 16 hours. The solution was rotary evaporated toremove dioxane to provide an off white solid. This solid wasrecrystallized from CHCl₃ to yield BOC-protected3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 55% yield.

Step C: BOC-protected3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100 M %) wasdissolved in DMF (20 mL) and NaH (95%, 100 M %) was added in one portionand the reaction mixture was stirred for 1 hour. Methyl iodide (300 M %)was added and this mixture was stirred for 12 hours. The reaction wasthen poured into water and extracted with ethyl acetate (3×) thenbackwashed with water (3×) and then brine (1×). Treatment with MgSO₄,rotoevaporation, and chromatography (5% MeOH/CH₂Cl₂) yieldedBOC-protected3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 75%yield.

Step D: BOC-protected3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100 M %)was suspended in 30 mL of 1:1 CH₂Cl₂/triflouroacetic acid. The reactionmixture was stirred for 4 hours. The reaction was then rotoevaporated toyield 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(100% yield).

Example 6-B Synthesis of5-(L-Alaninyl)-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-oneHydrochloride

Following the procedure of Example 7-I and using5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride(Example 6-C), the title compound was prepared.

Example 6-C Synthesis of5-Amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one Hydrochloride

Step A: Following General Procedure 5-A and usingN-t-Boc-5-amino-3,3-dimethyl-5,7-dihydro-6H-benz[b]azepin-6-one (GeneralProcedure 6-B, followed by Boc protection) and methyl iodide,N-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one wasprepared.

Step B: Following General Procedure 8-N and usingN-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one, thetitle compound was prepared.

Example 6-D Synthesis of3-(S)-Amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

Step A: 3-(S)-Amino-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one wasprepared from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene(Aldrich) using the method of R. J. DeVita et al., Bioorganic andMedicinal Chemistry Lett. 1995, 5(12) 1281-1286.

Step B: Following General Procedure 5-A and using the product from StepA, the title compound was prepared.

Example 6-E Synthesis of3-(S)-Amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

Step A: 3-(S)-Amino-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one wasprepared from N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene(Aldrich) using the method of R. J. DeVita et al., Bioorganic andMedicinal Chemistry Lett. 1995, 5(12) 1281-1286.

Step B: Following General Procedure 5-A and using the product from StepA, the title compound was prepared.

Example 6-F Synthesis of3-(S)-Amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

The title compound was prepared from N-Boc-cystine (Novabio) and2-fluoro-1-nitrobenzene (Aldrich) using the method of R. J. DeVita etal., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286,followed by General Procedure 5-A.

7. Dibenzazepinone Derivatives and Related Compounds

General Procedure 7-A Preparation of5-Amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Derivatives

Step A: Following General Procedure 5-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one and an alkyl halide, the7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.

Step B: The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.) wasdissolved in THF and isoamylnitrite (1.2 eq.) was added. The mixture wascooled to 0° C. in an ice bath. NaHMDS (1.1 eq., 1M in THF) was addeddropwise. After stirring for 1 hour or until the reaction was complete,the mixture was concentrated then acidified with 1N HCl and extractedwith EtOAc. The organic portion was dried and concentrated to yield acrude product which was purified by silica gel chromatography.

Step C: The resulting oxime was dissolved in EtOH/NH₃ (20:1) andhydrogenated in a bomb using Raney nickel and hydrogen (500 psi) at 100°C. for 10 hours. The resulting mixture was filtered and concentrated toprovide an oil which was purified by silica gel chromatography to yieldthe title compound.

General Procedure 7-B Preparation of Fluoro-substituted5,7-dihydro-6H-dibenz[b,d]azepin-6-one Derivatives

A modification of the procedure of Robin D. Clark and Jahangir,Tetrahedron, Vol. 49, No. 7, pp. 1351-1356, 1993 was used. Specifically,an appropriately substituted N-t-Boc-2-amino-2′-methylbiphenyl wasdissolved in THF and cooled to −78° C. s-Butyl lithium (1.3M incyclohexane, 2.2 eq.) was added slowly so that the temperature remainedbelow −65° C. The resulting mixture was allowed to warm to −25° C. andwas stirred at that temperature for 1 hour. The mixture was cooled to−78° C. Dry CO₂ was bubbled through the mixture for 30 seconds. Themixture was allowed to warm to ambient temperature then was carefullyquenched with water. The mixture was concentrated under reduced pressurethen was adjusted to pH 3 with 1N HCl. The mixture was extracted withEtOAc and the organic portion was dried and concentrated to yield acrude material. The crude material was dissolved in methanol and thesolution was saturated with HCl. The mixture was heated at reflux for 12hours then was allowed to cool. The mixture was concentrated to providecrude lactam which was purified by chromatography or crystallization.

General Procedure 7-C Resolution of5-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

In a round bottom flask was added the racemic freebase amine (1.0 eq.)in methanol followed by di-p-toluoyl-D-tartaric acid monohydrate (1.0eq.). The mixture was concentrated in vacuo to a residue and redissolvedin a moderate volume of methanol and allowed to stir at room temperatureopen to the atmosphere (8-72 hours). The solid was removed byfiltration. The enantiomeric excess was determined by chiral HPLC(Chiracel ODR) using 15% acetonitrile and 85% H₂O with 0.1%trifluoroacetic acid and a flow rate of 1.0 mL/min at 35° C. Theresolved di-p-toluoyl-D-tartaric salt was then dissolved in EtOAc andsaturated NaHCO₃ until pH 9-10 was reached. The layers were separatedand the organic layer was washed again with saturated NaHCO₃, H₂O, andbrine. The organic layer was dried over MgSO₄ and the drying agent wasremoved by filtration. The filtrate was concentrated in vacuo. The freeamine was dissolved in MeOH and HCl (12M, 1.0 eq.) was added. The saltwas concentrated in vacuo and the resulting film was triturated withEtOAc. The HCl salt was filtered and rinsed with EtOAc. The ee wasdetermined by chiral HPLC.

Example 7-A Synthesis of5-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride

Step A—Synthesis of 7-Methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A round bottom flask was charged with sodium hydride (0.295 g, 7.46mmol) in 9.0 ml of DMF and treated with5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.3 g, 6.22 mmol) (CAS#20011-90-9, prepared as described in Brown, et. al., TetrahedronLetters, No. 8, 667-670, (1971) and references cited therein). Afterstirring at 60° C. for 1 h, the solution was treated with methyl iodide(1.16 ml, 18.6 mmol) and stirring continued for 17 h with the exclusionof light. After cooling, the reaction was diluted with CH₂Cl₂/H₂O,washed with NaHSO₄ solution, H₂O, and dried over Na₂SO₄. Evaporation andflash chromatography (SiO₂, CHCl₃) gave 0.885 g (63%) of the titlecompound as a colorless solid.

NMR data was as follows:

¹H-nmr (CDCl₃): d=7.62 (d, 2H), 7.26-7.47 (m, 6H), 3.51 (m, 2H), 3.32(s, 3H). C₁₅H₁₃NO (MW=223.27); mass spectroscopy (MH+) 223. Anal. Calcdfor C₁₅H₁₃NO; C, 80.69; H, 5.87; N, 6.27. Found: C, 80.11; H, 5.95; N,6.23.

Step B—Synthesis of7-Methyl-5-oximo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

The compound isolated above (0.700 g, 3.14 mmol) was dissolved in 20 mlof toluene and treated with butyl nitrite (0.733 ml, 6.28 mmol). Thereaction temperature was lowered to 0° C. and the solution was treatedwith KHMDS (9.42 ml, 0.5 M) under N₂ atmosphere. After stirring for 1 hthe reaction was quenched with a saturated solution of NaHSO₄, dilutedwith CH₂Cl₂ and separated. The organic layer was dried over Na₂SO₄ andthe title compound purified by chromatography (SiO₂, 98:2 CHCl₃/MeOH)giving 0.59 g (80%) as a colorless solid.

C₁₅H₁₂N₂O₂ (MW=252.275); mass spectroscopy (MH+) 252. Anal. Calcd forC₁₅H₁₂N₂O₂; C, 71.42; H, 4.79; N, 11.10. Found: C, 71.24; H, 4.69; N,10.87.

Step C—Synthesis of5-Amino-7-Methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride

The oxime isolated above (0.99 g, 3.92 mmol) was hydrogenated in a Parrapparatus at 35 psi over 10% Pd/C (0.46 g) in 3A ethanol. After 32 h thereaction mixture was filtered through a plug of celite, the filtrateevaporated to a foam and treated with a saturated solution of HCl (g) inEt₂O. The resulting colorless solid was filtered, rinsed with cold Et₂Oand vacuum dried to give 0.66 g (61%), of the title compound.

NMR data was as follows:

¹H-nmr (DNSOd): d=9.11 (bs, 3H), 7.78-7.41(m, 8H), 4.83 (s, 1H), 3.25(s, 3H). C₁₅H₁₄N₂O HCl (MW=274.753); mass spectroscopy (MH+ free base)238. Anal. Calcd for C₁₅H₁₄N₂O HCl; C, 65.57; H, 5.50; N, 10.19 Found:C, 65.27; H, 5.67; N, 10.13.

Example 7-B Synthesis of (S)- and(R)-5-(L-Alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Step A—Synthesis of (S)- and(R)-5-(N-boc-L-Alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Boc-L-Alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF andtreated with HOBt hydrate (0.305 g, 2.26 mmol), and5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.45 g, 1.89mmol) (Example 7-A). The temperature was lowered to 0° C. and thereaction mixture treated with EDC (0.449 g, 2.26 mmol) (Aldrich) andstirred 17 hours under N₂. The reaction mixture was evaporated, theresidue diluted with EtOAc/H₂O, washed 1.0 N HCl, sat. NaHCO₃, brine anddried over Na₂SO₄. The diastereomers were separated on a Chiralcel ODcolumn using 10% IPA/heptane at 1.5 ml/minute.

Isomer 1: Retention time 3.37 minutes.

NMR data was as follows:

¹H-nmr (CDCl₃): d=7.62-7.33 (m, 9H), 5.26 (d, 1H), 5.08 (m, 1H), 4.34(m, 1H), 3.35 (s, 3H), 1.49 (s, 9H), 1.40 (d, 3H). Optical Rotation:[a]₂₀=−96 @589 nm (c=1, MeOH). C₂₃H₂₇N₃O₄ (MW=409.489); massspectroscopy (MH+) 409. Anal. Calcd for C₂₃H₂₇N₃O₄; C, 67.46; H, 6.64;N, 10.26. Found: C, 68.42; H, 7.02; N, 9.81.

Isomer 2: Retention time 6.08 minutes.

NMR data was as follows:

¹H-nmr (CDCl₃): d=7.74 (bd, 1H), 7.62-7.32 (m, 8H), 5.28 (d, 1H), 4.99(m, 1H), 4.36 (m, 111), 3.35 (s, 3H), 1.49 (s, 9H), 1.46 (d, 3H).Optical Rotation: [a]₂₀=69 @589 nm (c=1, MeOH). C₂₃H₂₇N₃O₄ (MW=409.489);mass spectroscopy (MH+) 409. Anal. Calcd for C₂₃H₂₇N₃O₄; C, 67.46; H,6.64; N, 10.26. Found: C, 67.40; H, 6.62; N, 10.02.

Step B—Synthesis of (S)- and(R)-5-(L-Alaninyl)-amino-7-methyl-4,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

The compounds isolated in Part A (each isomer separately) were dissolvedin dioxane and treated with excess HCl (g). After stirring for 17 hours,the title compounds were isolated as colorless solids after evaporationand vacuum drying.

Isomer 1:

C₁₈H₁₉N₃O₂.HCl (MW=345.832); mass spectroscopy (MH+ free base) 309.Optical Rotation: [a]₂₀=−55 @589 nm (c=1, MeOH).

Isomer 2:

C₁₈H₁₉N₃O₂.HCl (MW=345.832); mass spectroscopy (MH+ free base) 309.Optical Rotation: [a]₂₀=80 @589 nm (c=1, MeOH).

Example 7-C Synthesis of (S)- and(R)-5-(L-Valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Step A—Synthesis of (S)- and(R)-5-(N-boc-L-Valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Boc-L-Valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF andtreated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 mmol, 6.05mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (0.75 g, 2.75 mmol)(Example 7-A). The temperature waslowered to 0° C. and the reaction mixture treated with EDC (0.601 g,3.02 mmol)(Alrich) and stirred 17 hours under N₂. The reaction mixturewas evaporated, the residue diluted with EtOAc/H₂O, washed 1.0 N HCl,sat. NaHCO₃, brine and dried over Na₂SO₄. The diastereomers wereseparated on a Chiralcel OD column using 10% IPA/heptane at 1.5ml/minute.

Isomer 1: Retention time 3.23 minutes.

Optical Rotation: [a]₂₀=−120 @589 nm (c=1, MeOH). C₂₅H₃₁N₃O₄(MW=437.544); mass spectroscopy (MH+) 438.

Isomer 2: Retention time 6.64 minutes.

Optical Rotation: [a]₂₀=50 @589 nm (c=1, MeOH). C₂₅H₃₁N₃O₄ (MW=437.544);mass spectroscopy (MH+) 438.

Step B—Synthesis of (S)- and(R)-5-(L-Valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

The compounds isolated in Part A (each isomer separately) were dissolvedin dioxane and treated with excess HCl (g). After stirring for 17 hours,the title compounds were isolated as colorless solids after evaporationand vacuum drying.

Isomer 1:

C₂₀H₂₃N₃O₂.HCl (MW=373.88); mass spectroscopy (MH+ free base) 338.Optical Rotation: [a]₂₀=−38 @589 nm (c=1, MeOH).

Isomer 2:

C₂₀H₂₃N₃O₂.HCl (MW=373.88); mass spectroscopy (MH+ free base) 338.Optical Rotation: [a]₂₀=97 @589 nm (c=1, MeOH).

Example 7-D Synthesis of (S)- and(R)-5-(L-tert-Leucine)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Step A—Synthesis of (S)- and(R)-5-(N-boc-L-tert-Leucinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Boc-L-tert-Leucine (0.698 g, 3.02 mmol) (Fluka) was dissolved in THF andtreated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml, 6.05 mmol)and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (0.75 g, 2.75 mmol)(Example 7-A). The temperature waslowered to 0° C. and the reaction mixture treated with EDC (0.601 g,3.02 mmol) (Alrich) and stirred 17 hours under N₂. The reaction mixturewas evaporated, the residue diluted with EtOAc/H₂O, washed 1.0 N HCl,sat. NaHCO₃, brine and dried over Na₂SO₄. The diastereomers wereseparated on a Chiralcel OD column using 10% IPA/heptane at 1.5ml/minute.

Isomer 1: Retention time 3.28 minutes.

Optical Rotation: [a]₂₀=−128 @589 nm (c=1, MeOH). C₂₆H₃₃N₃O₄(MW=451.571); mass spectroscopy (MH+) 452.

Isomer 2: Retention time 5.52 minutes.

Optical Rotation: [a]₂₀=26 @589 nm (c=1, MeOH). C₂₆H₃₃N₃O₄ (MW=451.571);mass spectroscopy (MH+) 452.

Step B—Synthesis of (S)- and(R)-5-(L-tert-Leucinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

The compounds isolated in Part A (each isomer separately) were dissolvedin dioxane and treated with excess HCl (g). After stirring for 17 hours,the title compounds were isolated as colorless solids after evaporationand vacuum drying.

Isomer 1:

C₂₁H₂₅N₃O₂.HCl (MW=387.91); mass spectroscopy (MH+ free base) 352.Optical Rotation: [a]₂₀=−34 @589 nm (c=1, MeOH).

Isomer 2:

C₂₁H₂₅N₃O₂.HCl (MW=387.91); mass spectroscopy (MH+ free base) 352.Optical Rotation: [a]₂₀=108 @589 nm (c=1, MeOH).

Example 7-E Synthesis of5-(N-boc-Amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one

Step A—Synthesis of 5-Iodo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol)(Example 7-A) and Et₃N (2.66 ml, 19.12 mmol) were stirred for 5.0minutes at −15° C. in CH₂Cl₂ and treated with TMSI (1.36 ml, 9.54 mmol).After stirring for 15 minutes I₂ (1.81 g, 7.16 mmol) was added in asingle portion and the reaction allowed to warm to 5-10° C. over 3 h.The reaction was quenched with sat. Na₂SO₃, diluted with CH₂Cl₂ andseparated. The organics were washed with Na₂SO₃ and NaHSO₃ and driedover MgSO₄. After filtration, the organics were concentrated toapproximately 20 ml and diluted with an additional 20 ml of hexanes. Thetitle compound was isolated as a tan precipitate by filtration.

Step B—Synthesis of 5-Azido-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

The iodide isolate above was dissolved in DMF and treated with 1.2equivalents of NaN₃. After stirring 17 h at 23° C. the mixture wasdiluted with EtOAc/H₂O, separated, washed with brine and dried overMgSO₄. The title compound was triturated from hot EtOAc as a tan powder.

Step C—Synthesis of5-(N-boc-Amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one

The azide was dissolved in THF/H₂O and stirred at 23° C. for 17 h in thepresence of 3.0 equivalents of Ph₃P. The reaction was diluted with 50%HOAc/toluene, separated, the aqueous layer extracted with toluene andevaporated to an oily residue. This was taken to pH 7.0 by the additionof 1 N NaOH, the resulting HOAc salt was collected and vacuum dried.Finally, the compound was treated with Boc anhydride (1.05 equivalents)and Et₃N (2.1 equivalents) in THF. After stirring for 5 h at 23° C. thereaction was filtered and the title compound isolated as a colorlesspowder.

Example 7-F Synthesis of5-Amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Step A—Synthesis of5-(N-boc-Amino)-7-(2-methylpropyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs₂CO₃ (0.22g, 0.678 mmol) and warmed to 60° C. To the reaction mixture was added1-iodo-2-methylpropane (0.078 ml, 0.678 mmol) and stirring continued for17 h. After cooling to 23° C. the mixture was diluted with CH₂Cl₂,washed with several portions of brine and dried over Na₂SO₄. The titlecompound was purified by chromatography (SiO₂, CHCl₃/MeOH 9:1).

C₂₃H₂₈N₂O₃ (MW=380.41); mass spectroscopy (MH+) 381 Anal. Calcd forC₂₃H₂₈N₂O₃; C, 72.61; H, 7.42; N, 7.36. Found: C, 72.31; H, 7.64; N,7.17.

Step B—Synthesis of5-Amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

The compound isolated in Part A was deprotected in dioxane saturatedwith gaseous HCl. The title compound was isolated as a slightly coloredsolid after evaporation and vacuum drying.

Example 7-G Synthesis of5-Amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Step A—Synthesis of5-(N-boc-Amino)-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(1.03, 3.08 mmol) (Example 7-E) in DMF was treated with Cs₂CO₃ (1.10 g,3.39 mmol) and warmed to 60° C. To the reaction mixture was addedbromomethyl acetate (0.321 ml, 3.39 mmol) (Aldrich) and stirringcontinued for 17 h. After cooling to 23° C. the mixture was diluted withCH₂Cl₂, washed with several portions of brine and dried over Na₂SO₄. Thetitle compound was purified by chromatography (SiO₂, CHCl₃).

C₂₂H₂₄N₂O₅ (MW=396.44); mass spectroscopy (MH+) 397; Anal. Calcd forC₂₂H₂₄N₂O₅; C, 66.65; H, 6.10; N, 7.07. Found: C, 66.28; H, 5.72; N,6.50.

Step B—Synthesis of5-Amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

The compound isolated in Part A was deprotected in dioxane saturatedwith gaseous HCl. The title compound was isolated as a colorless solidafter evaporation and vacuum drying.

C₁₇H₁₆N₂O₃ HCl (MW=332.78); mass spectroscopy (MH+ free base) 297.

Example 7-H Synthesis of5-Amino-7-(3,3-dimethyl-2-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Step A—Synthesis of5-(N-boc-Amino)-7-(3,3-dimethyl-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs₂CO₃ (0.3 g,0.925 mmol) and warmed to 60° C. To the reaction mixture was added1-chloro-3,3-dimethyl-2-butanone (0.096 ml, 0.74 mmol) (Aldrich) andstirring continued for 17 h. After cooling to 23° C., the mixture wasdiluted with CH₂Cl₂, washed with several portions of brine and driedover Na₂SO₄. The title compound was isolated as a colorless solid.

C₂₅H₃₀N₂O₄ (MW=422.522); mass spectroscopy (MH+) 423.

Step B—Synthesis of5-Amino-7-(3,3-dimethyl-2-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

The compound isolated in Part A was deprotected in dioxane saturatedwith gaseous HCl. The title compound was isolated as a colorless solidafter evaporation and vacuum drying.

Example 7-I Synthesis ofL-Alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Step A: Following General Procedure D and using N-t-Boc-L-alanine and5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onewas prepared.

Step B: Following General Procedure 8-N and using theN-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,the title compound was prepared. Other substitutedN-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onescan also be prepared by this procedure.

Example 7-J Synthesis ofL-Valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Step A: Following General Procedure D and using N-t-Boc-L-valine and5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,N-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onewas prepared.

Step B: Following General Procedure 8-N and using theN-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,the title compound was prepared. Other substitutedN-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onescan also be prepared by this procedure.

Example 7-K Synthesis of5-Amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure 7-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown,et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and referencescited therein) and 1-chloro-4-phenylbutane (Aldrich), the title compoundwas prepared.

Example 7-L Synthesis of5-Amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure 7-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown,et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and referencescited therein) and (bromomethyl)cyclopropane (Aldrich), the titlecompound was prepared.

Example 7-M Synthesis of5-Amino-7-(2,2,2-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure 7-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown,et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and referencescited therein) and 1-bromo-2,2,2-trifluoroethane (Aldrich), the titlecompound was prepared.

Example 7-N Synthesis of5-Amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure 7-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown,et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and referencescited therein) and bromocyclohexane (Aldrich), the title compound wasprepared.

Example 7-O Synthesis of5-(L-Alaninyl)amino9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Step 1: 2-Bromo-5-fluorotoluene was stirred in THF at −78° C. s-BuLi(1.05 eq., 1.3 M in cyclohexane) was slowly added and the mixture wasstirred for 45 minutes. Trimethylborate (1.5 eq) was added and themixture was allowed to warm to ambient temperature. After stirring for 1hour, pinacol (2 eq.) was added. The mixture was stirred for 16 hoursthen was concentrated under reduced pressure. The resulting residue wasslurried in CH₂Cl₂ and filtered through Celite. The filtrate wasconcentrated to yield an oil which was purified by chromatography ondeactivated silica gel (Et₃N) to yield the arylboronate ester.

Step 2: 2-Bromoaniline (1 eq.) and di-t-butyl-dicarbonate (1.1 eq.) werestirred at 80° C. for 20 hours. The resulting mixture was allowed tocool and was directly distilled using house vacuum to provideN-t-Boc-2-bromoaniline.

Step 3: N-t-Boc-2-bromoaniline (Step 2, 1 eq.), the arylboronate ester(Step 1, 1.1 eq.), K₂CO₃ (1.1 eq.) andtetrakis(triphenylphosphine)palladium(0) (0.02 eq) were stirred in 20%water/dioxane under nitrogen. The solution was heated at reflux for 10hours. The mixture was allowed to cool then was concentrated. Theresulting residue was partitioned between water and chloroform. Theorganic portion was dried and concentrated to yield an oil which waspurified by silica gel chromatography using 1:1 CH₂Cl₂/hexanes.

Step 4: Following General Procedure 7-B and using the substitutedbiphenyl from step 3, the9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.

Step 5:9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq., Step 4),cesium carbonate (1.1 eq., Aldrich) and methyl iodide (1.1 eq., Aldrich)were stirred in dry DMF at ambient temperature for 16 hours. The mixturewas concentrated under reduced pressure to provide a residue which waspartitioned between EtOAc and water. The organic portion was dried andconcentrated to yield an oil which was purified by silica gelchromatography to9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

Step 6: Following General Procedure 7-A, Step B and9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step5,5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one wasprepared.

Step 7: Following the procedure of Example 7-I and using5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one fromStep 6, the title compound was prepared.

Example 7-P Synthesis of5-(L-Alaninyl)amino-1,3-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Following the procedure of Example 7-O and using 2-bromo-4-fluoroaniline(Step 2, Lancaster) and o-tolylboronic acid (Step 3, Aldrich), the titlecompound was prepared.

Example 7-Q Synthesis of5-(L-Alaninyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Following the procedure of Example 7-O and using 2-bromo-4-fluorotoluene(Step 1), the title compound was prepared.

Example 7-R Synthesis of5-(L-Alanyl)-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Following the procedure of Example 7-I and using5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-L), the title compound was prepared.

Example 7-S Synthesis of5-(L-Alaninyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Following the procedure of Example 7-I and using5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example7-K), the title compound was prepared.

Example 7-T Synthesis of5-(L-Valinyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Following the procedure of Example 7-J and using5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-L), the title compound was prepared.

Example 7-U Synthesis of5-(L-Valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Following the procedure of Example 7-J and using5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example7-U), the title compound was prepared.

Example 7-V Synthesis of5-(L-Valinyl)amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Step A: Following General Procedure 7-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown,et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and referencescited therein) and 1-bromohexane (Aldrich),5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.

Step B: Following the procedure of Example 7-J and using5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the titlecompound was prepared.

Example 7-W Synthesis of5-(L-Valinyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Following the procedure of Example 7-J and using5-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (asprepared in Example 7-Q), the title compound was prepared.

Example 7-X Synthesis of5-(L-Valinyl)amino-1,3-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Following the procedure of Example 7-J and using the5-amino-1,3-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (asprepared in Example 7-P), the title compound was prepared.

Example 7-Y Synthesis of5-(L-Valinyl)amino-1,3-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Following the procedure of Example 7-J and using the5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (asprepared in Example 7-O), the title compound was prepared.

Example 7-Z Synthesis of(5-Amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d]azepin-6-one

The 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-A) was dissolved in a 1:1 mixture ofEtOAc/HOAc. 5% Rh/C was added and the mixture was stirred at 60° C.under 60 psi of hydrogen. After 3 days, the mixture was filtered and thefiltrate was concentrated to provide an oil which was purified bySCX-cation exchange chromatography to yield the title compound.

Example 7-AA Synthesis of5-(S)-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

Following General Procedure 7-C using racemic5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 eq.) anddi-p-toluoyl-D-tartaric acid monohydrate (1.0 eq.) in methanol, thetitle compound was prepared as a solid. The product was collected byfiltration. Enantiomeric excess was determined by chiral HPLC.

Desired enantiomer 1: retention time of 9.97 minutes.

Undesired enantiomer 2: retention time of 8.62 minutes.

NMR data was as follows:

¹H-nmr (CDCl₃): d=9.39 (s, 2H), 7.75-7.42 (m, 8H), 4.80 (s, 1H), 3.30(s, 3H). C₁₅H₁₅ClN₂O (MW 274.75); mass spectroscopy (MH+) 239.1. AnalCalcd for C₁₅H₁₅ClN₂O₃; C, 65.57; H, 5.50; N, 10.20; Found: C, 65.51, H,5.61; N, 10.01.

8. Benzodiazepine Derivatives and Related Compounds

General Procedure 8-A N-1-Methylation of Benzodiazepines

A solution of benzodiazepine (1 eq.) in DMF (0.1 M concentration) at 0°C. was treated with potassium tert-butoxide (1.0 eq., 1.0 M solution inTHF). After stirring for 30 minutes at 0° C., iodomethane (1.3 eq.) wasadded and stirring continued for 25 minutes. The mixture was dilutedwith methylene chloride and washed with water and brine. The organicphase was dried over Na₂SO₄, filtered, and concentrated. The crudeproduct was then either purified by trituration with 1:1 ether/hexanesor chromatographed via HPLC using ethyl acetate/hexanes as the eluent.

General Procedure 8-B Cbz Removal Procedure

A flask was charged with the Cbz-protected 3-aminobenzodiazepine (1eq.). To this was added HBr (34 eq.; 30% solution in acetic acid).Within 20 minutes all of the starting material dissolves. The reactionwas stirred for 5 hours at ambient temperature. Ether was added to theorange solution causing the HBr amine salt to precipitate. The mixturewas decanted. This process of adding ether and decanting was repeatedthrice in an effort to remove acetic acid and benzyl bromide. Toluenewas added and the mixture concentrated in vacuo. This step was alsorepeated. The HBr salt was partitioned between ethyl acetate and 1 MK₂CO₃. The aqueous layer was back-extracted with ethyl acetate. Thecombined organics were washed with brine, dried over Na₂SO₄, filtered,and concentrated.

General Procedure 8-C Boc Removal Procedure

A solution of Boc-protected amine (1 eq.) in methylene chloride (0.15 Mconcentration) was cooled to 0° C. and treated with trifluoroacetic acid(30 eq.). After 10 minutes at 0° C., the cooling bath was removed andstirring continued at ambient for 20 minutes to 1 hour. The mixture wasconcentrated in vacuo to remove excess trifluoroacetic acid. The residuewas dissolved in methylene chloride and washed with saturated aqueousNaHCO₃ or 1 M K₂CO₃ and brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated.

General Procedure 8-D Azide Transfer Reaction Using KHMDS

The azido derivative was prepared using the procedure described in JohnW. Butcher et al., Tet. Lett., 37, 6685-6688 (1996).

General Procedure 8-E Azide Transfer Reaction Using LDA

To a solution of diisopropylamine (1.1 eq.) in 1 mL of dry THF cooled to−78° C. was added n-butyl lithium (1.6M in hexane) (1.1 eq.) dropwisemaintaining the reaction temperature at −78° C. The reaction mixture wasstirred for 30 min. at −78° C. and then the lactam (0.471 mM) was addeddropwise as a solution in 1 mL of dry THF. The reaction mixture wasstirred at −78° C. for 30 min. and then a pre-cooled solution of trisylazide (1.2 eq.) was added as a solution in 1 mL of dry THF. The reactionmixture was stirred at −78° C. for 20 min. and then quenched with aceticacid (4.0 eq.). The reaction mixture was then stirred at 40° C. for 2hrs. The reaction was then poured into EtOAc and washed with water,sodium bicarbonate and brine, and then dried over sodium sulfate,filtered and concentrated. The residue was purified by LC 2000chromatography.

General Procedure 8-F Azido Group Reduction

The azido group was reduced to the corresponding primary amine using theprocedure described in John W. Butcher et al., Tet. Lett., 37, 6685-6688(1996).

General Procedure 8-G N-Alkylation of Amides or Lactams Using SodiumHydride or Potassium tert-Butoxide

To a slurry of sodium hydride or potassium tert-butoxide (1.1 eq) in 15mL of dry DMF was added the appropriate amide (0.0042 moles) as asolution in 10 mL of DMF. The alkyl iodide was then added and a thickslurry resulted. The reaction became less thick as time elapsed and whencomplete by TLC the reaction had become homogeneous. The reactionmixture was poured over ice and extracted into ethyl acetate. Theorganic layer was washed with water, followed by brine. The organiclayer was then dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by HPLC (LC 2000),eluting with an ethyl acetate/hexane system.

General Procedure 8-H N-Alkylation of Amides or Lactams Using KHMDS

To the appropriate amide or lactam in THF cooled to −78° C. was addedKHMDS dropwise and the reaction mixture was stirred for 30 min. at −78°C. The alkyl iodide was then added dropwise while maintaining thetemperature at −70° C. The cooling bath was then removed and reactionwas allowed to warm to room temperature and stirring was continued for 2hours. The reaction mixture was then poured over ice and extracted intoethyl acetate. The organic extracts were washed with water, followed bybrine. The organic layer was then dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byHPLC (LC 2000), eluting with an ethyl acetate/hexane system.

General Procedure 8-I N-Alkylation of Amides or Lactams Using CesiumCarbonate

To a solution of the amide or lactam in DMF was added cesium carbonate(1.05 eq) and an alkyl iodide (1.1 eq). The mixture was allowed to stirovernight at room temperature and then the reaction mixture was dilutedwith ethyl acetate and washed with water, followed by brine. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by HPLC (LC 2000), elutingwith an ethyl acetate/hexane system.

General Procedure 8-J BOC Removal Procedure

To an N-Boc protected compound was added CH₂Cl₂/TFA (4:1) at roomtemperature. The reaction mixture was stirred at room temperature for 3hours and then concentrated. The residue was extracted intodichloromethane and washed with water, saturated sodium bicarbonate,dried over Na₂SO₄, filtered and concentrated to give the free amine.

General Procedure 8-K Azide Transfer Procedure

This azide transfer procedure is a modification of the proceduredescribed in Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L.J. Am. Chem. Soc. 1990, 112, 4011-4030. To a solution of the lactamsubstrate (1.0 eq.) in THF (˜0.1 M) under N₂ at −78° C. was added asolution of KN(TMS)₂ (1.1 eq. of 0.5 M in Toluene, Aldrich) dropwiseover a period of 2-10 minutes. A slight exotherm was often observed byan internal thermometer, and the resulting solution was stirred for 5-15minutes, while re-cooling to −78° C. Then, trisyl azide (1.1-1.5 eq.,CAS No. 36982-84-0, prepared as described by references in the Evansreference above) in THF (˜0.5 M), either precooled to −78° C. or at roomtemperature, was added via cannula over a period of 0.5-5 minutes.Again, a slight exotherm was generally noted. The resulting solution wasstirred for from 5-10 minutes, while re-cooling to −78° C. Then, AcOH(4.5-4.6 eq., glacial) was added, the cooling bath removed and themixture allowed to warm to room temperature with stirring for 12-16hours. The mixture was diluted with EtOAc, in a 2-5 volume multiple ofthe initial THF volume, and washed with dilute aq. NaHCO₃ (1-2×),0.1-1.0 M aq. HCl (0-2×), and brine (1×). The organic phase was thendried over MgSO₄, filtered, concentrated to provide the crude product.

General Procedure 8-L Azide Reduction to an Amine

A mixture of the azide in absolute EtOH (0.03-0.07 M) and 10% Pd/C (˜⅓by weight of the azide) was shaken in a Parr apparatus under H2 (35-45psi) at room temperature for 3-6 hours. The catalyst was removed byfiltration through a plug of Celite, rinsing with absolute EtOH, and thefiltrate concentrated to provide the crude amine product.

General Procedure 8-M Amide Alkylation Using Cesium Carbonate

This procedure is a modification of the procedure described in Claremon,D. A.; et al, PCT Application: WO 96-US8400 960603. To a mixture of2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 49799-48-6)in DMF (1.0 eq., 0.7 M) under N₂ at room temperature was added Cs₂CO₃(2.2 eq.) and the appropriate alkyl halide (2.2 eq.). The mixture wasstirred at room temperature for 5.5-16 hours. The mixture waspartitioned between EtOAc and sat. NaHCO₃. The aqueous layer wasextracted with EtOAc (1-2×) and the combined EtOAc extracts were driedover Na₂SO₄, filtered, and concentrated to provide the crude product.

General Procedure 8-N BOC Removal Procedure

A stream of anhydrous HCl gas was passed through a stirred solution ofthe N-t-Boc protected amino acid in 1,4-dioxane (0.03-0.09 M), chilledin a ice bath to 10° C. under N₂, for 10-15 minutes. The solution wascapped, the cooling bath removed, and the solution was allowed to warmto room temperature with stirring for 2-8 hours, monitoring by TLC forthe consumption of starting material. The solution was concentrated (andin some instances dissolved in CH₂Cl₂ then re-concentrated and placed invacuum oven at 60-70° C. to remove most of the residual dioxane) andused without further purification.

Example 8-A Synthesis of3-Amino-1,3-dihydro-5-(1-piperidinyl)-2H-1,4-benzodiazepin-2-one

Step A—Preparation of1,2-Dihydro-3H-1-methyl-5-(1-piperidinyl)-1,4-benzodiazepin-2-one

A solution of phosphorous pentachloride (1.2 eq) in methylene chloridewas added dropwise to a solution of1-methyl-1,2,3,4-tetrahydro-3H-1,4-benzodiazepin-2,5-dione (Showell, G.A.; Bourrain, S.; Neduvelil, J. G.; Fletcher, S. R.; Baker, R.; Watt, A.P.; Fletcher, A. E.; Freedman, S. B.; Kemp, J. A.; Marshall, G. R.;Patel, S.; Smith, A. J.; Matassa, V. G. J. Med. Chem. 1994, 37, 719.) inmethylene chloride. The resultant yellowish-orange solution was stirredat ambient temperature for 2.5 hours; the solvent was removed in vacuo.The orange residue was redissolved in methylene chloride, cooled to 0EC, and treated with a solution of piperidine (2 eq) and triethylamine(2 eq) in methylene chloride. The cooling bath was removed and thereaction stirred for 18 hours. The reaction mixture was washed withsaturated aqueous NaHCO₃ (back-extracted with methylene chloride) andbrine. The organic phase was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified via HPLC eluting with a gradientof 4 to 10% methanol/methylene chloride affording the title intermediateas a yellow solid having a melting point of 103-105° C.

C₁₅H₁₉N₃O (MW 257.37); mass spectroscopy 257. Anal. Calcd for C₁₅H₁₉N₃O:C, 70.01; H, 7.44; N, 16.33. Found: C, 69.94; H, 7.58; N, 16.23.

Step B—Preparation of1,2-Dihydro-3H-1-methyl-3-oximido-5-(1-piperidinyl)-1,4-benzodiazepin-2-one

Potassium tert-butoxide (2.5 eq) was added in two portions to a −20° C.solution of1,2-dihydro-3H-1-methyl-5-(1-piperidinyl)-1,4-benzodiazepin-2-one (1 eq)in toluene). After stirring at −20° C. for 20 min, isoamyl nitrite (1.2eq.; Aldrich) was added to the red reaction mixture. The reaction wasstirred at −20° C. for 5 hours at which time the reaction was done byTLC. The cooling bath was removed and the reaction quenched with 0.5 Mcitric acid. After stirring for 10 minutes, diethyl ether was added. Thesuspension was stirred at ambient temperature overnight then filteredwashing with ether. The resultant cream colored solid had a meltingpoint of 197-200° C.

¹H NMR data of the E/Z isomers was as follows:

¹H NMR (300 MHz, CDCl₃): d=7.64 (1H, bs), 7.48 (2H, d, J=7.4 Hz),7.35-7.20 (6H, m), 6.75 (1H, bs), 3.8-3.2 (8H, m), 3.46 (3H, s), 3.42(3H, s), 1.90-1.40 (12H, m). C₁₅H₁₈N₄O₂ (MW=286.37); mass spectroscopy286.

Step C—Preparation of1,2-Dihydro-3H-1-methyl-3-[O-(ethylaminocarbonyl)oximido]-5-(1-piperidinyl)-14-benzodiazepin-2-one

A mixture of1,2-dihydro-3H-1-methyl-3-oximido-5-(1-piperidinyl)-1,4-benzodiazepin-2-one(1 eq) in THF was treated with ethyl isocyanate (1.7 eq) andtriethylamine (0.6 eq). The mixture was heated to 64° C. for 4 hours.The mixture was concentrated and the residue purified by HPLC elutingwith 5% methanol/methylene chloride.

¹H NMR data of the E/Z isomers was as follows:

¹H NMR (300 MHz, CDCl₃): d=7.50 (2H, dd, J=8.4, 1.5 Hz), 7.35-7.22 (6H,m), 6.42 (1H, bt), 6.20 (1H, bt), 3.7-3.4 (8H, m), 3.46 (3H, s), 3.44(3H, s), 3.25 (4H, m), 1.9-1.4 (12H, m), 1.12 (3H, t, J=6.3 Hz), 1.10(3H, t, J=6.3 Hz). C₁₈H₂₃N₅O₃ (MW=357.46); mass spectroscopy 357.

Step D—Preparation of3-Amino-1,3-dihydro-2H-1-methyl-5-(1-piperidinyl)-1,4-benzodiazepin-2-one

The1,2-dihydro-3H-1-methyl-3-[O-(ethylaminocarbonyl)oximido]-5-(1-piperidinyl)-1,4-benzodiazepin-2-one(1 eq) was hydrogenated in methanol over 5% palladium on carbon (0.15eq) at 43 psi for 3.25 hours. The reaction was filtered through celiteand concentrated in vacuo. The residue was taken up in methylenechloride and filtered a second time through celite. The filtrate wasconcentrated and the resultant foam was used immediately.

Example 8-B Synthesis of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A—Preparation of(S)-3-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,(1S)-7.7-Dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate

The title intermediate was prepared according to Reider, P. J.; Davis,P.; Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 955 using3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (BockM. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Veber, D. F.;Freidinger, R. M.; Hirshfield, J.; Springer, J. P. J. Org. Chem. 1987,52, 3232.) as the starting material.

Step B—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate was freebased by partitioning between methylene chloride and 1M potassiumcarbonate. The free amine was then coupled with N-Boc-alanine followingGeneral Procedure D.

C₂₄H₂₈N₄O₄ (MW=436.56); mass spectroscopy 436. Anal. Calc. forC₂₄H₂₈N₄O₄: C, 66.03; H, 6.47; N, 12.84. Found: C, 65.79; H, 6.68; N,12.80.

Step C—Preparation of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,the title compound was prepared as a white foam.

Anal. Calc. for C₁₉H₁₉N₄O₂: C, 69.21; H, 6.64; N, 15.37. Found: C,70.11; H, 6.85; N, 15.01.

Example 8-C Synthesis of3-(L-Alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A—Preparation of3-(Benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

A solution of3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-Benzodiazepin-2-one(1 eq; Neosystem) in DMF was cooled to 0° C. and treated with potassiumtert-butoxide (1 eq; 1.0M solution in THF). The resultant yellowsolution was stirred at 0° C. for 30 minutes then quenched with methyliodide (1.3 eq). After stirring an addition 25 minutes the reaction wasdiluted with methylene chloride and washed with water and brine. Theorganic phase was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified via HPLC chromatography eluting with a gradient of20630% ethyl acetate/hexanes.

C₂₄H₂₀ClN₃O₃ (MW=433.92); mass spectroscopy 433. Anal. calcd forC₂₄H₂₀ClN₃O₃: C, 66.44; H, 4.65; N, 9.68. Found: C, 66.16; H, 4.50; N,9.46.

Step B—Preparation of3-Amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-B using3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam which was usedimmediately in Step C.

Step C—Preparation of3-[N-tert-Butylcarbamate)-L-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

Following General Procedure D using N-Boc-L-alanine and3-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam.

C₂₄H₂₈ClN₄O₄ (MW=471.18); mass spectroscopy 471; Anal. calcd forC₂₄H₂₈ClN₄O₄: C, 61.21; H, 5.78; N, 11.90. Found: C, 61.24; H, 5.59; N,11.67.

Step D—Preparation of3-(L-Alaninyl)amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-C using3-[N-tert-butylcarbamate)-L-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam. The crude materialwas used immediately.

Example 8-D Synthesis of3-(L-Alaninyl)amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Step A—Preparation of3-(Benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-A using3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one(Neosystem), the title intermediate was prepared as a white foam.

C₂₄H₁₉BrFN₃O₃ (MW=496.36); mass spectroscopy 497. Anal. calcd forC₂₄H₁₉BrFN₃O₃: C, 58.08; H, 3.86; N, 8.47. Found: C, 57.90; H, 4.15; N,8.20.

Step B—Preparation of3-Amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-B using3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam which was usedimmediately in Step C.

Step C—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

Following General Procedure D using N-Boc-L-alanine (Novo) and3-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam.

C₂₄H₂₆BrFN₄O₄, (MW=533.12); mass spectroscopy 533.2. Anal. calcd forC₂₄H₂₆BrFN₄O₄: C, 54.04; H, 4.91; N, 10.50. Found: C, 53.75; H, 4.92; N,10.41.

Step D—Preparation of3-(L-Alaninyl)-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam. The crude materialwas used immediately.

Example 8-E Synthesis of3-(N-Methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A—Preparation of3-[N′-(tert-Butylcarbamate)-N′-methyl-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D and using(S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(Example 8-B) and N-tert-Boc-N-methyl-alanine (Sigma), the titleintermediate was obtained as a white solid.

C₂₅H₃₀N₄O₄ (MW=450.2); mass spectroscopy (M+1) 451.2. Anal. calcd forC₂₅H₃₀N₄O₄: C, 66.65; H, 6.71; N, 12.44. Found: C, 66.66; H, 6.89; N,12.21.

Step A—Preparation of3-(N′-Methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-C and using3-[N′-(tert-butylcarbamate)-N-methyl-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam.

C₂₀H₂₂N₄O₂ (MW=350.46); mass spectroscopy (M+1) 351.4. Anal. calcd forC₂₀H₂₂N₄O₂: C, 68.55; H, 6.33; N, 15.99. Found, C, 68.36; H, 6.20; N,15.79.

Example 8-F Synthesis of3-(L-Alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one

Step A—Preparation of3-(Benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-A using3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one(Neosystem), the title intermediate was prepared as a white solid havinga melting point of 232-233° C.

C₂₄H₁₉Cl₂N₃O₃ (MW=468.36); mass spectroscopy 468. ¹H NMR (300 MHz,CDCl₃): d=7.67 (1H, m), 7.52 (1H, dd, J=2.4, 8.7 Hz), 7.42-7.26 (9H, m),7.07 (1H, d, J=2.4 Hz), 6.70 (1H, d, J=8.3 Hz), 5.35 (1H, d, J=8.4 Hz),5.14 (2H, ABq, J=19.6 Hz), 3.47 (3H, s). ¹³C NMR (75 MHz, CDCl₃):d=166.66, 165.65, 155.72, 140.52, 136.99, 136.0, 132.87, 131.99, 131.47,131.40, 131.38, 131.16, 130.54, 130.06, 128.45, 128.08, 128.03, 127.72,127.22, 123.28, 122.01, 68.95, 67.02, 35.32.

Step B—Preparation of3-Amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-B using3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam which was usedimmediately in Step C.

Step C—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one

Following General Procedure D using N-Boc-L-alanine and3-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam.

C₂₄H₂₆Cl₂N₄O₄ (MW=505.44); mass spectroscopy 505.2.

Step D—Preparation of3-(L-Alaninyl)-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam. The crude materialwas used immediately.

Example 8-G Synthesis of3-(L-Alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-Benzodiazepin-2-one

Step A—Preparation of3-(Benzyloxycarbonyl)-amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-A using3-(benzyloxycarbonyl)-amino-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(Neosystem), the title intermediate was prepared as a white solid havinga melting point of 205-206° C.

C₂₄H₂₇N₃O₃ (MW=405.54); mass spectroscopy 405. ¹H NMR (300 MHz, CDCl₃):d=7.54 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=7.7 Hz), 7.36-7.26 (7H, m),6.54 (1H, d, J=8.3 Hz), 5.15 (1H, d, J=8.0 Hz), 5.09 (2H, ABq, J=17.1Hz), 3.39 (3H, s), 2.77 (1H, m), 2.01 (1H, bd, J=13.6 Hz), 1.85 (1H, bd,J=12.4 Hz), 1.68-1.49 (4H, m), 1.34-1.02 (4H, m).

Step B—Preparation of3-Amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-B using3-(benzyloxycarbonyl)-amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam which was usedimmediately in Step C.

C₁₆H₂₁N₃O (MW+H=272.1763); mass spectroscopy 272.1766.

Step C—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

Following General Procedure D using N-Boc-L-alanine and3-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam.

C₂₄H₃₄N₄O₄ (MW=442.62); mass spectroscopy (M+H) 443.2.

Step D—Preparation of3-(L-Alaninyl)amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam. The crude materialwas used immediately.

C₁₉H₂₆N₄O₂ (M+H=343.2136); mass spectroscopy found 343.2139.

Example 8-H Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A—Preparation of2-[N-(a-Isopropylthio)-N-(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone

A solution of α-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq;prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975, 31,863.) in dry THF was cooled to 0° C. and treated with oxalyl chloride (1eq.) and 3 drops of DMF. After stirring for 15 minutes at 0° C., thecooling bath was removed and stirring continued at ambient temperaturefor 40 minutes. The solution was recooled to 0° C. A solution of2-amino-5-nitrobenzophenone (0.9 eq.; Acros) and 4-methylmorpholine (2.0eq.) in dry THF was added via cannulation to the acid chloride. Thecooling bath was removed and the reaction stirred at ambient for 5hours. The reaction was diluted with methylene chloride and washed with0.5 M citric acid, saturated aqueous NaHCO₃, and brine. The organicphase was dried over Na₂SO₄, filtered, and concentrated. The residue waspurified via preparative LC2000 eluting with a gradient of 15620% ethylacetate/hexanes giving an off-white foam.

C₂₆H₂₅N₃O₆S (MW=507.61); mass spectroscopy found 507.9. Anal. calcd forC₂₆H₂₅N₃O₆S: C, 61.53; H, 4.96; N, 8.28. Found: C, 61.70; H, 4.99; N,8.22.

Step B—Preparation of2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone

Ammonia gas was bubbled into a solution2-[N-(α-isopropylthio)-N′-(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone(1 eq) in THF at 0° C. After 35 minutes mercury(II) chloride (1.1 eq)was added. The ice bath was removed and ammonia gas was continued tobubble through the suspension for 4 hours. The bubbler was removed andthe reaction continued to stir for 16 hours. The mixture was filteredthrough celite washing with THF. The filtrate was concentrated in vacuo.The crude solid was used in step C without further purification.

Step C—Preparation of3-(Benzyloxycarboyl)-amino-2,3-dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone(1 eq) was treated with glacial acetic acid and ammonium acetate (4.7eq). The suspension was stirred at ambient temperature for 21 hours.After concentrating the reaction in vacuo, the residue was partitionedbetween ethyl acetate and 1 N NaOH. The aqueous layer was back-extractedwith ethyl acetate. The combined organics were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was purified viaflash chromatography eluting with a gradient of 263% isopropylalcohol/methylene chloride.

C₂₃H₁₈N₄O₅ (MW=430.45); mass spectroscopy found (M+H) 431.2. Anal. calcdfor C₂₃H₁₈N₄O₅: C, 64.18; H, 4.22; N, 13.02. Found: C, 64.39; H, 4.30;N, 13.07.

Step D—Preparation of3-(Benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-A and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam.

C₂₄H₂₀N₄O₅ (MW=444.48); mass spectroscopy found (M+H) 445.2. Anal. calcdfor C₂₄H₂₀N₄O₅: C, 64.86; H, 4.54; N, 12.60. Found: C, 65.07; H, 4.55;N, 12.46.

Step E—Preparation of3-Amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-B and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam which was usedimmediately in Step F.

Step F—Preparation of3-[N-(tert-Butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D using N-Boc-L-alanine and3-amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow solid.

C₂₄H₂₇N₅O₆ (MW=481.56); mass spectroscopy found (M+H) 482.3. Anal. calcdfor C₂₄H₂₇N₅O₆: C, 59.88; H, 5.61; N, 14.55. Found: C, 60.22; H, 5.75;N, 13.91.

Step G—Preparation of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam. The crude materialwas used immediately.

Example 8-I Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Step A—Preparation of3-Amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

A flask was charged with3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one(1 eq.; Example 8-D, Step A) and 10% palladium on carbon. Methanol wasadded, and the flask was placed under a balloon of H₂. The reaction wasstirred for 21 hours. The mixture was filtered through celite washingwith methanol. The filtrate was concentrated to a white solid.

C₁₆H₁₄FN₃O (MW=283.33); mass spectroscopy found (M+H) 284.1.

Step B—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

Following General Procedure D using N-Boc-L-alanine and3-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white solid.

C₂₄H₂₇FN₄O₄ (MW=454.50); mass spectroscopy found (M+H) 455.4. Anal.calcd for C₂₄H₂₇FN₄O₄: C, 63.44; H, 5.95; N, 12.33. Found: C, 63.64; H,6.08; N, 12.16.

Step C—Preparation of3-(L-Alaninyl)-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam. The crude materialwas used immediately.

Example 8-J Synthesis of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Step A—Preparation of 2-Amino-3′-fluorobenzophenone

A solution of 3-bromofluorobenzene (1 eq.) in THF was cooled to −78° C.under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6 Msolution in pentane) at a rate of 40 ml/h. The internal temperature didnot rise above −74° C. The orange solution was stirred at −78° C. for 30minutes prior to the addition of anthranilonitrile (0.6 eq.) as asolution in THF. The reaction was warmed to 0° C. and stirred for 2hours. 3N HCl was added to the mixture and stirring continued for 30minutes. The reaction was diluted with ethyl acetate and the layers wereseparated. The aqueous layer was back-extracted thrice with ethylacetate. The combined extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified via HPLCeluting with 93:7 hexanes/ethyl acetate.

C₁₃H₁₀FNO (MW=215.24); mass spectroscopy found (M+H) 216.3. ¹H NMR (300MHz, CDCl₃) d 7.44-7.19 (6H, m), 6.74 (1H, d, J=8.0 Hz), 6.61 (1H, dd,J=0.94, 7.9 Hz), 6.10 (2H, bs).

Step B—Preparation of2-[N-(a-Isopropylthio)-N-(benzyloxycarbonyl)-glycinyl]-amino-3-fluorobenzophenone

A solution of a-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq;prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975, 31,863.) in dry THF was cooled to 0° C. and treated with oxalyl chloride (1eq.) and 3 drops of DMF. After stirring for 15 minutes at 0° C., thecooling bath was removed and stirring continued at ambient temperaturefor 40 minutes. The solution was recooled to 0° C. A solution of2-amino-3′-fluorobenzophenone (0.9 eq.) and 4-methylmorpholine (2.0 eq.)in dry THF was added via cannulation to the acid chloride. The coolingbath was removed and the reaction stirred at ambient for 5 hours. Thereaction was diluted with methylene chloride and washed with 0.5 Mcitric acid, saturated aqueous NaHCO₃, and brine. The organic phase wasdried over Na₂SO₄, filtered, and concentrated. The residue was purifiedvia preparative LC2000 eluting with a gradient of 15620% ethylacetate/hexanes giving an off-white foam.

C₂₆H₂₅N₂O₄S (MW=480.60); mass spectroscopy found (M+NH₄ ⁺) 498.3. ¹H NMR(300 MHz, CDCl₃) d 11.39 (1H, s), 8.59 (1H, d, J=6.0 Hz), 7.63-7.55 (2H,m), 7.48-7.27 (9H, m), 7.14 (1H, dt, J=1.2, 8.4 Hz), 5.94 (1H, d, J=7.2Hz), 5.58 (1H, d, J=8.7 Hz), 5.17 (2H, ABq, J=14.7 Hz), 3.25 (1H, sep,J=6.6 Hz), 1.44 (3H, d, J=6.0 Hz), 1.28 (3H, d, J=6.6 Hz).

Step C—Preparation of2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-3-fluorobenzophenone

Ammonia gas was bubbled into a solution2-[N-(α-isopropylthio)-N′-(benzyloxycarbonyl)-glycinyl]-amino-3′-fluorobenzophenone(1 eq) in THF at 0° C. After 35 minutes mercury(II) chloride (1.1 eq)was added. The ice bath was removed and ammonia gas was continued tobubble through the suspension for 4 hours. The bubbler was removed andthe reaction continued to stir for 16 hours. The mixture was filteredthrough celite washing with THF. The filtrate was concentrated in vacuo.The crude solid was used in step D without further purification.

Step D—Preparation of3-(Benzyloxycarbonyl)-amino-2,3-dihydro-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-3′-fluorobenzophenone(1 eq) was treated with glacial acetic acid and ammonium acetate (4.7eq). The suspension was stirred at ambient temperature for 21 hours.After concentrating the reaction in vacuo, the residue was partitionedbetween ethyl acetate and 1 N NaOH. The aqueous layer was back-extractedwith ethyl acetate. The combined organics were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was purified viaflash chromatography eluting with a gradient of 263% isopropylalcohol/methylene chloride.

C₂₃H₁₈FN₃O₃ (MW=4O3.44); mass spectroscopy found (M+H) 404.4. Anal.calcd for C₂₃H₁₈FN₃O₃C0.5H₂O: C, 66.98; H, 4.64; N, 10.18. Found: C,67.20; H, 4.64; N, 9.77.

Step E—Preparation of3-(Benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-A and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam.

C₂₄H₂₀FN₃O₃ (MW=417.47); mass spectroscopy found (M+H) 418.3. Anal.calcd for C₂₄H₂₀FN₃O₃: C, 69.06; H, 4.83; N, 10.07. Found: C, 69.33; H,4.95; N, 9.82.

Step F—Preparation of3-Amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-B and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam which was usedimmediately in Step G.

Step G—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure D using N-Boc-L-alanine and3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow solid.

C₂₄H₂₇FN₄O₄ (MW=454.50); mass spectroscopy found (M+H) 455.3. Anal.calcd for C₂₄H₂₇FN₄O₄: C, 63.42; H, 5.99; N, 12.33. Found: C, 63.34; H,6.01; N, 12.08.

Step H—Preparation of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam. The crude materialwas used immediately.

Example 8-K Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Step A—Preparation of 2-Amino-4-fluorobenzophenone

A solution of 4-bromofluorobenzene (1 eq.) in THF was cooled to −78° C.under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6 Msolution in pentane) at a rate of 40 ml/h. The internal temperature didnot rise above −74° C. The orange solution was stirred at −78° C. for 30minutes prior to the addition of anthranilonitrile (0.6 eq.) as asolution in THF. The reaction was warmed to 0° C. and stirred for 2hours. 3N HCl was added to the mixture and stirring continued for 30minutes. The reaction was diluted with ethyl acetate and the layers wereseparated. The aqueous layer was back-extracted thrice with ethylacetate. The combined extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified via HPLCeluting with 93:7 hexanes/ethyl acetate.

C₁₃H₁₀FNO (MW=215.24); mass spectroscopy found (M+H) 216.3. Anal. calcdfor C₁₃H₁₀FNO: C, 72.55; H, 4.68; N, 6.51. Found: C, 72.80; H, 4.51; N,6.74.

Step B—Preparation of2-[N-(α-Isopropylthio)-N′-(benzyloxycarbonyl)-glycinyl]-amino-4-fluorobenzophenone

A solution of α-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq;prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975, 31,863.) in dry THF was cooled to 0° C. and treated with oxalyl chloride (1eq.) and 3 drops of DMF. After stirring for 15 minutes at 0° C., thecooling bath was removed and stirring continued at ambient temperaturefor 40 minutes. The solution was recooled to 0° C. A solution of2-amino-4′-fluorobenzophenone (0.9 eq.) and 4-methylmorpholine (2.0 eq.)in dry THF was added via cannulation to the acid chloride. The coolingbath was removed and the reaction stirred at ambient for 5 hours. Thereaction was diluted with methylene chloride and washed with 0.5 Mcitric acid, saturated aqueous NaHCO₃, and brine. The organic phase wasdried over Na₂SO4, filtered, and concentrated. The residue was purifiedvia preparative LC2000 eluting with a gradient of 15→20% ethylacetate/hexanes giving an off-white foam.

C₂₆H₂₅N₂O₄S (MW=480.60); mass spectroscopy found (M+NH₄ ⁺) 498.2. ¹H NMR(300 MHz, CDCl₃) d 11.28 (1H, s), 8.56 (1H, d, J=8.4 Hz), 7.78-7.73 (2H,m), 7.61-7.53 (2H, m), 7.36-7.32 (5H, m), 7.20-7.14 (3H, m), 5.98 (1H,d, J=7.5 Hz), 5.57 (1H, d, J=7.8 Hz), 5.16 (2H, ABq, J=14.7 Hz), 3.25(1H, sep, J=6.0 Hz), 1.43 (3H, d, J=6.3 Hz), 1.27 (3H, d, J=6.6 Hz).

Step C—Preparation of2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-4′-fluorobenzophenone

Ammonia gas was bubbled into a solution2-[N-(α-isopropylthio)-N′-(benzyloxycarbonyl)-glycinyl]-amino-3′-fluorobenzophenone(1 eq) in THF at 0° C. After 35 minutes mercury(II) chloride (1.1 eq)was added. The ice bath was removed and ammonia gas was continued tobubble through the suspension for 4 hours. The bubbler was removed andthe reaction continued to stir for 16 hours. The mixture was filteredthrough celite washing with THF. The filtrate was concentrated in vacuo.The crude solid was used in step D without further purification.

Step D—Preparation of3-(Benzyloxycarbonyl)amino-2,3-dihydro-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one

2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-4′-fluorobenzophenone(1 eq) was treated with glacial acetic acid and ammonium acetate (4.7eq). The suspension was stirred at ambient temperature for 21 hours.After concentrating the reaction in vacuo, the residue was partitionedbetween ethyl acetate and 1 N NaOH. The aqueous layer was back-extractedwith ethyl acetate. The combined organics were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was purified viaflash chromatography eluting with a gradient of 263% isopropylalcohol/methylene chloride.

C₂₃H₁₈FN₃O₃ (MW=4O3.44); mass spectroscopy found (M+H) 404.4. Anal.calcd for C₂₃H₁₈FN₃O₃C1.25H₂O: C, 64.85; H, 4.85. Found: C, 64.80; H,4.55.

Step E—Preparation of3-(Benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-A and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam.

C₂₄H₂₀FN₃O₃ (MW=417.47); mass spectroscopy found (M+H) 418.2. Anal.calcd for C₂₄H₂₀FN₃O₃: C, 69.06; H, 4.83; N, 10.07. Found: C, 69.35; H,4.93; N, 9.97.

Step F—Preparation of3-Amino-1,3-dihydro-1-methyl-5-(4-fluorophenyl)-2H-1,4-benzodiazepin-2-one

Following General Procedure 8-B and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam which was usedimmediately in Step G.

Step G—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure D using N-Boc-L-alanine and3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow solid.

C₂₄H₂₇FN₄O₄ (MW=454.50); mass spectroscopy found (M+H) 455.4. Anal.calcd for C₂₄H₂₇FN₄O₄C1.5H₂O: C, 59.86; H, 6.28; N, 11.64. Found: C,60.04; H, 5.62; N, 11.27.

Step H—Preparation of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam. The crude materialwas used immediately.

Example 8-L Synthesis of3-(N′-L-Alaninyl)amino2,3-dihydro-1-isobutyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A: 1,3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (preparedaccording to the procedure of M. G. Bock et al., J. Org. Chem. 1987, 52,3232-3239) was alkylated with isobutyl iodide using General Procedure8-G to afford1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

Step B: Following General Procedures 8-D and 8-F and using the productfrom Step A,3-amino-1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one wasprepared.

Step C: The product from Step B and N-Boc-L-alanine (Sigma) were coupledusing General Procedure D, followed by removal of the Boc group usingGeneral Procedure 8-J, to afford3-(N′-L-alaninyl)amino-1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

By substituting isopropyl iodide, n-propyl iodide, cyclopropylmethyliodide and ethyl iodide for isobutyl iodide in Step A above, thefollowing additional intermediates were prepared:

3-(N′-L-alaninyl)amino-1,3-dihydro-1-isopropyl-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(N′-L-alaninyl)amino-1,3-dihydro-1-propyl-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(N′-L-alaninyl)amino-1,3-dihydro-1-cyclopropylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one

3-(N′-L-alaninyl)amino-1,3-dihydro-1-ethyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

Example 8-M Synthesis of3-(N′-L-Alaninyl)amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one

Step A: 1,3,4,5-Tetrahydro-5-phenyl-2H-1,5-benzodiazepin-2-one (CAS No.32900-17-7) was methylated using General Procedure 8-I to afford1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one.

Step B: Following General Procedures 8-E and 8-F and using the productfrom Step A,3-amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-onewas prepared.

Step C: The product from Step B and N-Boc-L-alanine (Sigma) were coupledusing General Procedure D, followed by removal of the Boc group usingGeneral Procedure 8-N, to afford3-(N′-L-alaninyl)amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one.

Example 8-N Synthesis of3-(N′-L-Alaninyl)amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

3-Amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(CAS No. 131604-75-6) was coupled with N-Boc-L-alanine (Sigma) usingGeneral Procedure D, followed by removal of the Boc group using GeneralProcedure 8-N, to afford the title compound.

Example 8-O Synthesis of3-((R)-Hydrazinopropionyl)amino-2,3-dihydro-1-methyl-5-phenyl)-1H-1,4-benzodiazepin-2-one

3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one wascoupled to (R)-N,N′-di-BOC-2-hydrazinopropionic acid (Example N) usingGeneral Procedure D. Removal of the BOC group using General Procedure5-B afforded the title compound.

Example 8-P Synthesis of3-Amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Step A:—Synthesis of 2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 49799-48-6)was prepared from 1,2-phenylenediamine (Aldrich) and malonic acid(Aldrich) using the procedure of Claremon, D. A.; et al, PCTApplication: WO 96-US8400960603.

Step B:—Synthesis of2,4-Dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

2,4-Dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(CAS No. 113021-84-4) was prepared following General Procedure 8-M usingthe product from Step A and 2-iodopropane (Aldrich). Purification was byflash chromatography eluting with EtOAc/hexanes (3:7 gradient to 1:1),then recrystalization from EtOAc/hexanes.

Step C:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure 8-K using the product from Step B,3-azido-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(CAS No. 186490-50-6) was prepared as a white solid. The product waspurified by flash chromatography eluting with hexanes/EtOAc (4:1) toprovide a separable 23:1 mixture of pseudo-axial/pseudo-equatorialazides. The pure pseudo-axial azide was used in the next step.

Step D:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure 8-L using the product from Step C,3-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(CAS No. 186490-51-7) was prepared as a white solid. Purification was byflash chromatography eluting with CH₂Cl₂/MeOH (98:2 gradient to 95:5).The isolated pseudo-axial amine atropisomer was completely converted tothe pseudo-equatorial amine atropisomer by heating in toluene to 100-105EC for 15 minutes, and the pseudo-equatorial amine atropisomer was usedin the next step. The isomers were distinguished by ¹H-NMR in CDCl₃.Selected ¹H-NMR (CDCl₃): Pseudo-axial amine 4.40 (s, 1H);Pseudo-equatorial amine 3.96 (s, 1H).

Example 8-Q Synthesis of3-(R-2-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Step A:—Synthesis of N-(t-Butoxycarbonyl)-R-2-thienylglycine

N-(t-Butoxycarbonyl)-R-2-thienylglycine (CAS No. 74462-03-1) wasprepared from L-a-(2-thienyl)glycine (Sigma) by the procedure describedin Bodansky, M. et al; The Practice of Peptide Synthesis; SpringerVerlag; 1994, p. 17.

Step B:—Synthesis of3-[N′-(t-Butoxycarbonyl)-R-2-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure J above using the product from Example 8-Pand the product from Step A above,3-[N′-(t-butoxycarbonyl)-R-2-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (9:1 gradient to 5:1).

Step C:—Synthesis of3-(R-2-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Following General Procedure 8-N above using the product from Step B, thetitle compound was prepared as a white solid.

Example 8-R Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Step A:—Synthesis of2,4-Dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

2,4-Dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CASNo. 23954-54-3) was prepared following General Procedure 8-M using theproduct from Example 8-P, Step A and iodomethane (Aldrich). The whitesolid product precipitated during partial concentration of the reactionafter work-up, and was isolated by filtration.

Step B:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

For this substrate, General Procedure 8-K was modified in the followingmanner. Initially the product from Step A was suspended (not a solution)in THF at −78° C., and following addition of the KN(TMS)₂ solution, thissuspension was allowed to warm to −35° C. over a period of 12 minutes,during which the suspension became a solution, and was re-cooled to −78°C.; then treated as described in the General Procedure.3-Azido-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas purified by flash chromatography eluting with CHCl₃/EtOAc (7:1),then trituration from hot CHCl₃ with hexanes and cooled to −23° C. Theproduct was isolated as a white solid.

Step C:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure 8-L using the product from Step B,3-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. The crude product was used withoutfurther purification.

Step D:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure I above using N-Boc-L-alanine (Novabiochem)and the product from Step C,3-[N′-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (2:1 gradient to 1:1).

Step E:—Synthesis of3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Following General Procedure 8-N above using the product from Step D, thetitle compound was prepared as an off-white amorphous solid.

Example 8-S Synthesis of3-(L-Alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Step A:—Synthesis of2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared following General Procedure 8-M using the product fromExample 8-P, Step A and 1-iodo-2-methylpropane (Aldrich). Purificationwas by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to1:1), then recrystalization from EtOAc/hexanes.

Step B:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure 8-K (a precipitate formed during theaddition of the KN(TMS)₂, but dissolved upon addition of the trisylazide) using the product from Step A,3-azido-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. The product was purified by flashchromatography eluting with hexanes/EtOAc (4:1) and a second flashchromatography eluting with CH₂Cl₂/hexanes/EtOAc (10:10:1 gradient to8:6:1).

Step C:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure 8-L using the product from Step B,3-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. Purification was by flash chromatographyeluting with CH₂Cl₂/MeOH (98:2 gradient to 95:5, with 5% NH₃ in theMeOH).

Step D:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure I above using N-Boc-L-alanine (Novabiochem)and the product from Step C,3-[N′-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (3:1 gradient to 3:2).

Step E:—Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Following General Procedure 8-N above using the product from Step D, thetitle compound was prepared as an amorphous white solid.

Example 8-T Synthesis of3-(S-Phenylglycinyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Step A:—Synthesis of3-[N′-(t-Butoxycarbonyl)-S-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure J above using the product from Example 8-S,Step C and the Boc-L-phenylglycine (Novabiochem, CAS No. 2900-27-8),3-[N′-(t-butoxycarbonyl)-S-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (9:1 gradient to 5:1).

Step B:—Synthesis of3-(S-Phenylglycinyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Following General Procedure 8-N above using the product from Step A,3-(S-phenylglycinyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride was prepared as an off-white solid.

Example 8-U Synthesis of3-(L-Alaninyl)amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Step A:—Synthesis of2,4-Dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

2,4-Dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared following General Procedure 8-M using the product fromExample 8-P, Step A, and (bromomethyl)cyclopropane (Lancaster).Purification was by flash chromatography eluting with EtOAc/hexanes (3:7gradient to straight EtOAc), then recrystalization from EtOAc/hexanes.

Step B:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

For this substrate General Procedure 8-K was modified in the followingmanner. Initially the product from Step A was suspended (not a solution)in THF at −78° C., and following addition of the KN(TMS)₂ solution, thissuspension was allowed to warm to −30° C., during which the suspensionbecame a solution, and was re-cooled to −78° C. Upon re-cooling to −78°C. a precipitate began to form, therefore the reaction flask containingthe mixture was partially raised above the cooling bath until theinternal temperature rose to −50° C.; then the trisyl azide solution wasadded. The cooling bath was removed and the mixture allowed to warm to−20° C. whereupon the mixture had become a nearly homogenous solution,and the AcOH was added. Then, treated as described in the generalprocedure.3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas purified by trituration with hot to room temperature EtOAc, followedby recrystalization from hot to −23° C. CHCl₃/EtOAc/EtOH (5:5:1) andisolated as a white solid.

Step C:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure 8-L using the product from Step B,3-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. Purification was by flash chromatographyeluting with CH₂Cl₂/MeOH (98:2 gradient to 95:5, with 5% NH₃ in theMeOH) followed by recrystalization from warm CH₂Cl₂/hexanes (1:1) to−23° C.

Step D:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure I above using N-Boc-L-alanine (Novabiochem)and the product from Step C,3-[N′-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (3:1 gradient to 2:1).

Step E:—Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Following General Procedure 8-N above using the product from Step D, thetitle compound was prepared as an off-white solid.

Example 8-V Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Step A:—Synthesis of2,4-Dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

To a stirred suspension of the product from Example 8-P, Step A (1.0eq., 17.08 g) in DMSO (500 mL) at room temperature was added neopentyliodide (43.01 g, 2.24 eq., Aldrich) and Cs₂CO₃ (72.65 g, 2.3 eq.,Aldrich). The resulting mixture was heated to 75° C. for 30 minutes,then additional Cs₂CO₃ (31.59 g, 1.0 eq.) was added and the mixturerapidly stirred at 75° C. for 6 hours. The mixture was allowed to cooland H₂O (500 mL) and EtOAc (1000 mL) were added. The phases werepartitioned and the organic phase washed with H₂O (1×500 mL), 1 M aq.HCl (2×500 mL), and brine (1×500 mL). Then, the organic phase was driedover MgSO₄, filtered, concentrated, and purified by flash chromatographyeluting with hexanes/EtOAc (3:2 gradient to 2:3) to provide2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineas a white solid.

Step B:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure 8-K using the product from Step A,3-azido-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. The product was purified by flashchromatography eluting with hexanes/CH₂Cl₂/EtOAc (10:5:1 gradient to5:5:1) to provide a separable 13:1 mixture ofpseudo-axial/pseudo-equatorial azides. The pure pseudo-axial azide wasused in the next step. Selected ¹H-NMR (CDCl₃): Pseudo-axial azide 5.12(s, 1H); Pseudo-equatorial azide 4.03 (s, 1H).

Step C:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure 8-L using the product from Step B,3-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. Purification was by flash chromatographyeluting with CH₂Cl₂/MeOH (98:2 gradient to 95:5, with 5% NH₃ in theMeOH). The isolated white solid product was identified as a ˜4:1 mixtureof pseudo-axial and pseudo-equatorial amines atropisomers by ¹H-NMR. Themixture was heated in toluene to 100 EC for 20 minutes, thenre-concentrated to provide the pure pseudo-equatorial amine atropisomer,as a white solid, and this was for the next step. Selected ¹H-NMR(CDCl₃): Pseudo-axial amine 4.59 (s, 1H); Pseudo-equatorial amine 4.03(s, 1H).

Step D:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure I above using N-Boc-L-alanine (Novabiochem)and the product from Step C,3-[N′-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (4:1 gradient to 5:2).

Step E:—Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Following General Procedure 8-N above using the product from Step D, thetitle compound was prepared as an off-white solid.

Example 8-W Synthesis of3-(L-Alaninyl)amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Step A:—Synthesis of2,4-Dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

This procedure is a modification of the procedure described in Chan, D.M. T. Tetrahedron Lett. 1996, 37, 9013-9016. A mixture of the productfrom Example 8-P, Step A (1.0 eq., 7.50 g), Ph₃Bi (2.2 eq., 41.26 g,Aldrich); Cu(OAc)₂ (2.0 eq., 15.48 g, Aldrich), Et₃N (2.0 eq., 8.62 g)in CH₂Cl₂ (100 mL) was stirred under N₂ at room temperature for 6 days(monitoring by TLC). The solids were removed by filtration through aplug of Celite rinsing with CH₂Cl₂/MeOH (3×75 mL). The filtrate wasconcentrated, dissolved in hot CH₂Cl₂/MeOH (9:1) and filtered through alarge plug of silica gel eluting with CH₂Cl₂/MeOH (9:1, 2L). Thefiltrate was concentrated and the residue purified by flashchromatography eluting with straight CH₂Cl₂ gradient to CH₂Cl₂/MeOH(9:1). 2,4-Dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinecrystallized during concentration of the fractions containing theproduct, and was isolated by filtration as a white solid.

Step B:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

For this substrate, General Procedure 8-K was modified in the followingmanner. Initially the product from Step A was suspended (not a solution)in THF at −70° C., and following addition of the KN(TMS)₂ solution, thissuspension was allowed to warm to −20° C. over a period of 10 minutes,during which the suspension became a solution, and was re-cooled to −70°C.; then treated as described in the general procedure. The titlecompound was purified by trituration with hot CHCl₃/hexanes (1:1) toyield3-azido-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineas a white solid.

Step C:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure 8-L using the product from Step B,3-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. Purification was by flash chromatographyeluting with CH₂Cl₂/MeOH (98:2 gradient to 95:5, with 5% NH₃ in theMeOH).

Step D:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure I above using N-Boc-L-alanine (Novabiochem)and the product from Step C,3-[N′-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (4:1 gradient to 3:1).

Step E:—Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

Following General Procedure 8-N above using the product from Step D, thetitle compound was prepared as a white amorphous solid.

Example 8-X Synthesis of3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following the method of R. G. Sherrill et al., J. Org. Chem., 1995, 60,730-734 and using glacial acetic acid and HBr gas, the title compoundwas prepared.

Example 8-Y Synthesis of3-(L-Valinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A—Synthesis of3-[N′-(tert-Butylcarbamate)-L-valinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate (Example8-B, Step A) was free based by partitioning between methylene chlorideand 1M potassium carbonate. The free amine was then coupled withN-Boc-valine following General Procedure D to give the title compound.

C₂₆H₃₂N₄O₄ (MW 464.62); mass spectroscopy 464.3. Anal. Calcd forC₂₆H₃₂N₄O₄: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.29; H, 6.79; N,11.20.

Step B—Synthesis of3-(L-valinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-C and using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one,the title compound was prepared as a white foam.

C₂₁H₂₃N₄O₂ (MW 363.48); mass spectroscopy (M+H) 364.2.

Example 8-Z Synthesis of3-(L-tert-Leucinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A—Synthesis of3-[N′-(tert-Butylcarbamate)-L-tert-leucinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate (Example8-B, Step A) was free based by partitioning between methylene chlorideand 1M potassium carbonate. The free amine was then coupled withN-Boc-tert-leucine following General Procedure D to give the titlecompound.

C₂₇H₃₅N₄O₄ (MW 479.66); mass spectroscopy 479.

Step B—Synthesis of3-(L-tert-Leucinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure 8-C and using3-[N′-(tert-butylcarbamate)-L-tert-leucinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one,the title compound was prepared as a white foam.

Anal. Calcd for C₂₂H₂₅N₄O₂$0.5H₂O: C, 68.19; H, 7.02; N, 14.40. Found:C, 68.24; H, 7.00; N, 14.00.

Example 8-AA Synthesis of3-(L-Alaninyl)-amino-2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepine

2,3-Dihydro-1,5-dimethyl-1H-1,4-benzodiazepine was prepared followingGeneral Procedures 8-I (using methyl iodide), 8-D and 8-F. Coupling ofthis intermediate with Boc-L-alanine (Novo) using General Procedure D,followed by deprotection using General Procedure 5-B afforded the titlecompound which was used without further purification.

Example 8-AB Synthesis of3-(L-3-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Step A:—Synthesis of N-(t-Butoxycarbonyl)-L-3-thienylglycineN-(t-Butoxycarbonyl)-L-3-thienylglycine was prepared fromL-a-(3-thienyl)glycine (Sigma) by the procedure described in Bodansky,M. et al; The Practice of Peptide Synthesis; Springer Verlag; 1994, p.17.

Step B:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-3-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure D above using the product from Example 8-V,Step C and the product from Step A above,3-[N′-(t-butoxycarbonyl)-L-3-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared.

Step C:—Synthesis of3-(L-3-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

Following General Procedure 8-N above using the product from Step B, thetitle compound was prepared.

Using the following combinatorial procedures, the following additionalintermediates and examples were prepared.

General Procedure C-A

To a 4 mL vial containing 60-100 mg (0.06-0.1 mmol) of polymer bound1-(1-pyrrolidinyl propyl)-3-ethyl carbodiimide was added 2 m-L of a0.015 mM stock solution of starting material 1 in DMF/chloroform and 1mL of a 0.0148 mM stock solution of starting material 2 in chloroform.The resulting slurry were shaken for 48 h and filtered. The filteredresin was washed with chloroform and the filtrate was concentrated todryness under vacuum. All product structures and purities were confirmedby HPLC using UV detection and IEX MS. Samples were submitted fortesting with out any further purification.

General Procedure C-B

To a 4 mL vial was added 840 μL of 0.05 mM stock solution of startingmaterial 1 in DMF/chloroform, 100 μL of a 0.21 mM stock solution ofstarting material 2 in chloroform and 100 μL of a 0.63 mM stock solutionof 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroform. Afterallowing to stand undisturbed for 48 h, the reaction mixture wasconcentrated and the residue redissolved in 2 mL of a 10%methanol/methylene chloride solution. This solution was then filteredthrough a pre-washed (methanol) 500 mg SCX column (Varian SamplePreparation; Harbor City, Calif.) using an additional 8 mL of the samesolvent. The filtrate was concentrated under reduced pressure and theresidue was dissolved in 20% methanol/methylene chloride and passedthrough a plug of silica gel (100 mg, Varian Sample Preparation). Thecollected filtrate was concentrated under reduced pressure and the crudeproducts were submitted for testing without further purification.Product structure and purity were confirmed by HPLC and IEX MS.

General Procedure C-C

To a 4 mL vial was added 540 μL of 0.05 mM stock solution of startingmaterial 1 in DMF/chloroform, 100 μL of a 0.44 mM stock solution ofstarting material 2 in chloroform and 100 μL of a 0.38 mM stock solutionof 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroform. Afterstanding undisturbed for 48 h, the reaction mixture was concentrated andthe residue redissolved in 2 mL of a 10% methanol/methylene chloridesolution. This solution was then filtered through a pre-washed(methanol) 500 mg SCX column using an additional 8 mL of the samesolvent. The filtrate was concentrated under reduced pressure and theresidue was dissolved in 20% methanol/methylene chloride and passedthrough a plug of silica gel (100 mg, Varian Sample Preparation). Thecollected filtrate was concentrated under reduced pressure and the crudeproducts were submitted for testing without further purification.Product structure and purity were confirmed by HPLC and IEX MS.

General Procedure C-D

To a 4 mL vial was added 540 μL of 0.05 mM stock solution of startingmaterial 1 in DMF/chloroform, 100 μL of a 0.44 mM stock solution ofstarting material 2 in chloroform, 100 μL of a 0.38 mM stock solution of1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100 μLof a 0.38 mM stock solution of PP-HOBt in DMF. After standingundisturbed for 48 h, the reaction mixture was concentrated and theresidue redissolved in 2 mL of a 10% methanol/methylene chloridesolution. This solution was then filtered through a pre-washed(methanol) 500 mg SCX column using an additional 8 mL of the samesolvent. The filtrate was concentrated under reduced pressure and theresidue was dissolved in 20% methanol/methylene chloride and passedthrough a plug of silica gel (100 mg, Varian Sample Preparation). Thecollected filtrate was concentrated under reduced pressure and the crudeproducts were submitted for testing without further purification.Product structure and purity were confirmed by HPLC and IEX MS.

General Procedure C-E

To a 4 mL vial was added 870 μL of 0.05 mM stock solution of startingmaterial 1 in DMF/chloroform, 1000 μL of a 0.05 mM stock solution ofstarting material 2 in chloroform, 1000 μL of a 0.05 mM stock solutionof 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100μL of a 0.48 mM stock solution of HOBt in DMF. After standingundisturbed for 48 h, the reaction mixture was concentrated and theresidue redissolved in 2 mL of a 10% methanol/methylene chloridesolution. This solution was then filtered through a pre-washed(methanol) 500 mg SCX column using an additional 8 mL of the samesolvent. The filtrate was concentrated under a stream of nitrogen toapproximately ⅓ its original volume and then passed over a plug (200 mg)of AG 1-8×anion exchange resin (BioRad; Hercules, Calif.; Columns werepre-washed with 1N NaOH, water and methanol) using an additional 6 mL of10% methanol/methylene chloride solution. The resulting filtrate wasconcentrated under vacuum and the crude products were submitted fortesting without further purification. Product structure and purity wereconfirmed by HPLC and IEX MS.

General Procedure C-F

Starting material 1 (9.1 μL, 0.109 mmol) was added neat to a mixture ofstarting material 2 (22.5 mg, 0.054 mmol) and piperidinylmethylpolystyrene (45 mg, 3.6 mmol/g (Fluka)) in 1 mL of methylene. Themixture was shaken for 80 h at ambient temperatures and then treatedwith methylisocyanate polystyrene (100 mg, 1.0 mmol/g (Novabiochem)) for24 h with shaking. The reaction mixture was filtered and the resinwashed with methylene chloride. The crude product was loaded onto a 500mg SCX ion exchange column (Varian Sample Preparation), washed 3× with 3mL of methanol and then eluted with 4 mL of 2 M ammonia methanol.Further purification of the final product was achieved usingsemi-preparative HPLC (0-100% acetonitrile (0.08% TFA)/water (0.1% TFA);25 mL/min.; 20×50 ODS-A column) to give 17 mg of the final product as anoff white foam.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃) 1.45-1.65 (m, 3H), 1.70-2.00 (m, 4H), 2.55-2.80(m, 4H), 3.25 (s, 2H), 3.50 (s, 3H), 4.65-4.80 (m, 1H), 5.45-5.55 (m,1H), 7.20-7.80 (m, 11H).

General Procedure C-G

To a 4 mL vial containing 0.03 mmol of starting material 2 was added 100μL of 0.25 mM stock solution of starting material 1 in chloroform, 100μL of a 0.3 mM stock solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in chloroform and 100 μL of a 0.3 mM stock solution of HOBtin DMF. After standing undisturbed for 48 h, the reaction mixture wasconcentrated and the residue redissolved in 2 mL of a 10%methanol/methylene chloride solution. This solution was then filteredthrough a pre-washed (methanol) 500 mg SCX column using an additional 8mL of the same solvent. The filtrate was concentrated under a stream ofnitrogen to approximately ⅓ its original volume and then passed over aplug (200 mg) of AG 1-8×anion exchange resin (BioRad; Hercules, Calif.;Columns were pre-washed with 1N NaOH, water and methanol) using anadditional 6 mL of 10% methanol/methylene chloride solution. Theresulting filtrate was concentrated under vacuum and the crude productswere submitted for testing without further purification. Productstructure and purity were confirmed by HPLC and IEX MS.

General Procedure C-H

The intermediates shown in Table C-1 (i.e., Starting material 2) weresynthesized in parallel in using the following procedure:

Step A: To a solution of3-(tert-butoxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one(CA No. 125:33692: 100 mg, 0.28 mmol) in 1 mL of anhydrous DMF was added600 μL of a solution of 0.5 M potassium bis(trimethylsilyl)amide (0.30mmol) in toluene. Neat alkyl halide (0.56 mmol; as indicated in TableC-1) was added immediately in one portion and the reaction mixture wasleft undisturbed overnight. When an alkyl chloride was used, 1equivalent of sodium iodide was added to the reaction mixture. Afterconcentration under reduced pressure, the crude reaction residue waspartitioned between methylene chloride (2 mL) and aqueous saturatedbicarbonate (2 mL) and then passed through a 5 g Extralut QE cartridge(EM Science; Gibbstown, N.J.) using 10 mL of methylene chloride. Theresulting filtrate was concentrated under reduced pressure and the crudeproduct was further purified using automated semi-preparative HPLC (YMC20×50 mm Silica column; gradient elution; 0-5% (5.5 min.), 5-20% (3.5min.), 20-100% (2 min.), 100% (4 min.) ethyl acetate/methylene chloride,flow rate of 25 mL/min.). Product provided the expected M+1 peak by IEXMS and were carried on without further purification andcharacterization.

Step B: The product obtained from Step A was dissolved in 5 mL of a 15%TFA/methylene chloride solution and allowed to stand undisturbed for 16h. After concentration under reduced pressure, the TFA salt wasdissolved in methanol and loaded directly onto a 1 g SCX column. Thecolumn was washed 3× with 2 mL portions of methanol and the product waseluted from the column using 6 mL of 2.0 M solution of ammonia/methanol.After concentration under reduced pressure, the product werecharacterized by IEX MS and carried on without further purification.

Step C: To the crude product obtained from Step B (1.05 equiv.) wasadded sequentially a 0.3 mM stock solution of HOBt H₂O (1.05 equiv.) inDMF, a 0.3 mM stock solution of N-t-BOC-L-alanine (1.0 equiv.) in THFand 0.3 mM stock solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.05 equiv.) in THF. After standing undisturbed for 24 h,the reaction mixture was concentrated and the residue redissolved in 2mL of a 10% methanol/methylene chloride solution. This solution was thenfiltered through a pre-washed (methanol) 1 g SCX (Varian SamplePreparation) column using an additional 8 mL of the same solvent. ForExample C-V a 1 g Si column (Varian Sample Preparation) was used). Thefiltrate was concentrated under a stream of nitrogen to approximately ⅓its original volume and then passed over a plug (500 mg) of AG 1-8×anionexchange resin (BioRad; Hercules, Calif.; Columns were pre-washed with1N NaOH, water and methanol) using an additional 10 mL of methanol. Theresulting filtrate was concentrated under reduced pressure and the crudeproduct was carried on without further purification aftercharacterization by IEX MS.

Step D: The crude product obtained from Step C was dissolved in 5 mL ofa 15% TFA/methylene chloride solution and allowed to stand undisturbedfor 16 h. After concentration under reduced pressure, the TFA salt wasdissolved in methanol and loaded directly onto a 1 g SCX column. Thecolumn was washed 3× with 2 mL portions of methanol and the product wereeluted from the column using 6 mL of 2.0 M solution of ammonia/methanol.After concentration under reduced pressure, the product werecharacterized by IEX MS and carried on without further purification.

General Procedure C-I

To a 4 mL vial containing 0.03 mmol of starting material 2 (from GeneralProcedure C-H) was added 100 μL of 0.25 mM stock solution of startingmaterial 1 in chloroform, 100 μL of a 0.3 mM stock solution of1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100 μLof a 0.3 mM stock solution of HOBt in DMF. After standing undisturbedfor 48 h, the reaction mixture was concentrated and the residueredissolved in 2 mL of a 10% methanol/methylene chloride solution. Thissolution was then filtered through a pre-washed (methanol) 500 mg Sicolumn using an additional 8 mL of the same solvent. The filtrate wasconcentrated under a stream of nitrogen to approximately ⅓ its originalvolume and then passed over a plug (200 mg) of AG 1-8×anion exchangeresin (Columns were pre-washed with 1N NaOH, water and methanol) usingan additional 6 mL of 10% methanol/methylene chloride solution. Theresulting filtrate was concentrated under vacuum and the crude productswere submitted for testing without further purification. Productstructure and purity were confirmed by HPLC and IEX MS.

General Procedure C-J

A vial was charged with a CHCl₃ solution of Starting material 1 (71mmol), a DMF solution of HOBt monohydrate (71 μmol), a CHCl₃ solution ofdiisopropylcarbodiimide (71 μmol), and a CHCl₃ solution of startingmaterial 2 (60/mol). The vial was capped and the solution allowed tostand at room temperature for two days. The reaction mixture was loadedonto a cation exchange column, washed with MeOH and eluted with 2 NNH₃/MeOH. The eluents were concentrated and dried to give the desiredproduct as determined by MS (IS) and HPLC.

General Procedure C-K

To a 4 mL vial was added 870 μL of 0.05 mM stock solution of startingmaterial 1 in DMF/chloroform, 1000 μL of a 0.05 mM stock solution ofstarting material 2 in chloroform, 1000 μL of a 0.05 mM stock solutionof 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100μL of a 0.48 mM stock solution of HOBt in DMF. After standingundisturbed for 48 h, the reaction mixture was concentrated and theresidue redissolved in 2 mL of a 10% methanol/methylene chloridesolution. This solution was then filtered through a pre-washed(methanol) 500 mg SCX column using an additional 8 mL of the samesolvent. The filtrate was concentrated under a stream of nitrogen toapproximately ⅓ its original volume and then passed over a plug (200 mg)of AG 1-8×anion exchange resin (BioRad; Hercules, Calif.; Columns werepre-washed with 1N NaOH, water and methanol) using an additional 6 mL of10% methanol/methylene chloride solution. The resulting filtrate wasconcentrated under vacuum and the crude products were submitted fortesting without further purification. Product structure and purity wereconfirmed by HPLC and IEX MS.

General Procedure C-L

The following amino acids were employed in this procedure: L-alanine(Aldrich), L-valine (Aldrich), L-norvaline (Aldrich), L-methione(Aldrich), L-phenylalanine (Aldrich), L-(+)--phenylglycine (Aldrich),L--(2-thienyl)glycine (Sigma), L--(3-thienyl)glycine (Sigma),L-cyclohexylglycine hydrochloride (Senn Chemical AG),O-tert-butyl-L-serine (Sigma), O-tert-butyl-L-threonine (Bachem) andO-tert-butyl-L-tyrosine (Bachem).

The amino acid (60 μmoles), 305 mg (150 μmoles) ofN,O-bistrimethylsilylacetamide and 1.5 mL of DMF were introduced intoseparate fritted screw capped vials. The mixtures were heated mildly andupon cooling 132 mg (15 μmoles) of p-nitrophenylcarbonate Wang resin(actual load of 1.14 mmole/g) (Novabiochem) was added to the individualvials. In addition, 73 mg (60 mmoles) of dimethylaminopyridine wasintroduced into vials containing L-cyclohexylglycine hydrochloride. Thevials were shaken at room temperature for 48 hours. Each reactionmixture was filtered through the internal frit and the resulting resinwas washed with (9×1.0 mL) of DMF, (9×1.0 mL) of methanol and (6×1.0 mL)of diethyl ether. Each reaction vial containing the resin bound aminoacid was then dried in a vacuum oven at 30° C.

General Procedure C-M

Into each fritted screw capped vial containing a resin bound amino acid(from General Procedure C-L) was introduced 81 mg (60 μmoles) of1-hydroxybenzotriazole hydrate (HOBT H₂O), 115 mg (60 μmoles) of1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl),and 2 mL of THF. A3-amino-2,4-dioxo-1,5-bis-(alkyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin(30 μmoles) selected from3-amino-2,4-dioxo-1,5-bis(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin(Example 8S, Step C),3-amino-2,4-dioxo-1,5-bis(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin(Example 8-R, Step C) and3-amino-2,4-dioxo-1,5-bis(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin(Example 8-U, Step C) was added to the vials. Each vial was then cappedand shaken at room temperature for 4 days. Each reaction mixture wasfiltered through the internal frit and the resulting resin was washedwith (3×2.0 mL) of DMF, (3×2.0 mL) of a 10% solution of acetic acid inmethanol, (3×2.0 mL) of a 10% solution of acetic acid in THF, and (3×2.0mL) of a 10% solution of acetic acid in dichloromethane.

General Procedure C-N

Each resin from General Procedure C-M was suspended in 2.0 mL oftrifluoroacetic acid for 30 minutes. Each reaction was filtered throughthe internal frit into a 10 mL vial and the resin was washed with (3×1.0mL) of methanol. The filtrate was concentrated under a flow of nitrogenat 30° C. The concentrated residue was dissolved in 1.5 mL of methanoland partitioned into 3 portions. Each portion was subjected to affinitychromatography on a pretreated SCX column (pretreatment consisted offlushing with 2 mL of a 10% solution of acetic acid in methanol followedby 2 mL of methanol). Once loaded, all columns were flushed with 5 mL ofmethanol, discarding each wash. Each compound was liberated from thecolumn with 5 mL of a 1 N solution of ammonia in a 1/1 solution ofmethanol and chloroform. Each solution was transferred to a tarred vialfollowed by concentration under a stream of nitrogen, followed by finalconcentration under vacuum.

General Procedure C-O

To each vial containing a specific amino acid benzodiazepine (fromGeneral Procedure C-N) is added 1 mL of a 0.4 M solution of1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC) and 0.9 equivalentsof a carboxylic acid. The vials are capped and shaken for 4 days. Thereaction mixture is then concentrated under a continuous flow ofnitrogen. The residue is subjected to affinity chromatography on apretreated SCX column (pretreatment includes flushing with 2 mL of a 10%solution of acetic acid in methanol followed by 2 mL of methanol). Onceloaded, all columns are eluted with 5 mL of methanol. Each solution istransferred to a tared vial followed by concentration under a stream ofnitrogen with final concentration under vacuum.

General Procedure C-P

A solution of the carboxylic acid (0.75 mL, 0.05 M in DCM) is reactedwith L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(0.75 mL, 0.06 M in DCM) (from Example 7-I), PP-HOBT (0.3 mL, 0.15 M inDMF, this reagent is used only with a substituted carboxylic acids), andEDC (0.3 mL, 0.15 M). The reaction is mixed for 18 hours, then purifiedon a Varian SCX column (500 mg column prewashed with MeOH (3×2.5 mL) and20% MeOH:DCM (3×2.5 mL)) eluting with 2.5 mL of 20% MeOH:DCM.

General Procedure C-Q

Step A: FMOC-Gly Wang resin (20 g, 10.8 mmole, Novabiochem A16415) wasreacted with a 30% solution of piperidine in N-methylpyrrolidinone (NMP)for 30 minutes. The solution was drained and the resin washed with NMP(5×200 mL). Benzophenone imine (19.5 g, 108 mmole) in NMP (150 mL) wasadded to the resin followed by glacial acetic acid (5.6 g, 94 mmole) andthe reaction was mixed overnight at room temperature. Reagents weredrained and the resin washed with NMP (5×150 mL) followed by DCM (5×150mL). The resin was dried under vacuum to afford (benzophenone imine)-GlyWang resin with a theoretical loading of 0.56 mmole per gram.

Step B: A suspension of the resin from Step A in NMP (9 mL) was reactedwith an alkyl bromide (5.6 mL of 1 M solution in NMP) selected from1-bromo-2-ethylbutane, 1-bromo-3-methylbutane, cyclopropylmethylbromide, 1-bromo-2-cyclohexylethane, 1-bromo-4-fluorobutane, and1-bromo-2-methylbutane; and BEMP (5.6 mL of 1 M solution in NMP) andBu₄NI (5.6 mL of 1 M solution in NMP) for 20 hours at room temperature.Reagents were drained and the resin washed with NMP (3×15 mL). To amixture of the resin in THF (7 mL) was added hydroxylamine hydrochloride(2 mL of a 1.6 M solution in water) and the reaction was mixed for 20hours at room temperature. Reagents were drained and the resin washedsequentially with THF (2×5 mL), 0.5 M solution of diisopropylethylaminein THF (5 mL), THF (5 mL), and NMP (3×5 mL).

Step C: The resin from Step B was divided into 12 equal reactions usingan isopicnic solution in NMP:CH₂Cl₂. To each reaction was addedsequentially a carboxylic acid (0.75 mL of a 0.45 M solution in NMP),HOBT (0.75 mL of a 0.45 M solution in NMP) and DIC (0.75 mL of a 0.45 Msolution in NMP). The reaction was mixed for 18 hours at roomtemperature. Reagents were drained and the resin washed with NMP (5×0.5mL), and DCM (5×0.5 mL). The resin was mixed with TFA:H₂O (95:5, 0.5 mL)for 4 hours. The filtrate was collected, resin washed with TFA:H₂O(95:5, 0.5 mL) and the filtrates combined. Solvents were evaporated toyield the N-acyl amino acid.

General Procedure C-R

Various acylated amino acids (approximately 0.02 mmole) (from GeneralProcedure C-Q) in separate vials were reacted with5-amino-7-methyl-5,7-dihydro-6H-dibenz[bd]azepin-6-one (0.1 mL, 0.3 M inDCM) (Example 7-A), PP-HOBT (0.2 mL, 0.15 M in DMF), and EDC-HCl (0.4mL, 0.08 M in DCM). Reactions were mixed for 18 hours at roomtemperature. Reactions were diluted with 0.5 mL MeOH, loaded onto aVarian SCX column (500 mg, Varian Sample Preparations, pre-washed withMeOH (2.5 mL) and 10% MeOH:CHCl (2.5 mL)), and eluted with 10%MeOH:CHCl₃ (2.5 mL). Solvents were evaporated from the products and thecrude products purified by semi-prep reverse phase chromatography(gradient 0 to 100%, 0.1% TFA in H₂O to 0.08% TFA in CH₃CN). The correctmolecular ion was detected for each product by ionspray mass spec andanalytical reverse phase chromatography (gradient 0 to 100%, 0.01% TFAin H₂O to 0.08% TFA in CH₃CN) showed the products to be greater than 90%pure.

General Procedure C-S

Step A: Each amino acid (150 μmol) was weighed into an 8-mL capacityvial and dissolved in 1.5 mL of 10% DMF in dichloromethane (DCM). Toeach vial was added 0.8 mL (175 μmol) of a solution of5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride(481 mg, 1.75 mmol) (from Example 7-A) and 670 mg (1.75 mmol) of PP-HOBT(from Example C-AF) dissolved in 7.5 mL DMF. This was followed by theaddition to each vial of 2 mL (approximately 200 μmol) of a solution ofEDC hydrochloride in DCM (383 mg, 2.0 mmol in 20 mL DCM). After rockingthe vials at room temperature for 14 hours, approximately 100-125 mg ofpolystyrene-piperidine resin (approximately 3.6 mmol/g, 350 μmol, 2.33eq.) was added to each vial and rocking continued for 15 minutes.Methanol (2.5 mL) was added to each vial and the material put on a 1 gSCX column (Varian) pre-equilibrated with 5 mL of MeOH and 5 mL of 10%MeOH/chloroform. After pushing the liquid through the column withnitrogen, the column was washed with 5 mL of 10% MeOH/chloroform. Thecombined eluents (collected in 25 mL roundbottom flasks) were evaporatedat reduced pressure with a warm water bath at 30-35° C. and then furtherevaporated in a vacuum oven at 40-45° C. When the net weight of theresidues was below 100 mg, 5 mL of dioxane and, if necessary, 1 mL ofMeOH was added to redissolve the residue and solvent was again removedon the rotary evaporator and in the vacuum oven. After drying in thevacuum oven overnight, an HPLC was taken of each product. HPLC showprimarily the desired product and with about 15% deblocked product(i.e., product with the BOC group removed).

Step B: To each round bottom flask was added 5 mL of 4 N HCl in dioxane.After sitting at room temperature for 2-3 hours, an HPLC was taken andwas solvent removed on the rotary evaporator (bath temp 30-35° C.) andin the vacuum oven overnight (at approximately 40° C.). The HPLC of thet-butyl threonine adduct showed incomplete removal of the t-butyl group.An additional 5 mL of 4 N HCl in dioxane was added and the reaction (atroom temperature) monitored by HPLC at 4 hours and approximately 20hours. Complete removal of the t-butyl group was observed after 20hours. All products were pure by HPLC with only a single peak orresolved diastereomeric peaks observed except for some trace impuritiesin the methione case. Yields varied from 80 to 100%. Each round bottomcontained approximately 150 μmoles of the amino acid linked to5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

Step C: A stock solution of 567 mg (1.48 mmol) PP-HOBT in 8.5 mL DMF(approximately 0.175 M PP-HOBT in DMF) was prepared and 0.81 g (0.86 mL,150 μmol) of this PP-HOBT solution was added to each of the nineround-bottom vessels containing the products from Step B. Clearsolutions were obtained for all, except where the linked amino acid wasα amino isobutyric acid. In this case, an additional 0.86 mL of DMF wasadded but still the mixture remained heterogeneous. The contents of eachof the nine round bottoms “n” (where n=1 to 9) were divided into fourequal portions (approximately 37 μmols each) and placed in vials. Stocksolutions (0.1 M) of the carboxylic acids were then made up in 10%DMF/DCM. The appropriate stock solution (0.3 mL, 30 μmol) was then addedto each of the vials. A 0.1 M stock solution (20 mL) of EDChydrochloride in DMF was prepared. This stock solution (0.4 mL, 40 μmol)was then added to each of the vials which were then capped and put on arotator for 12 hours. Normal SCX workup and evaporation of solventafforded products as white solids or clear to light caramel resins. Eachof these products was taken up in methanol/chloroform and divided intothree tared vials, plus a vial for MS and HPLC characterization. Afterevaporation of solvent, the final weights in each vial were determined.Product identity was verified by ionspray mass spec and purity assessedby reverse phase HPLC.

Example C-AF Preparation of PP-HOBT

To a stirred solution of 7.68 g (30 mmol) sulfonyl chloride in 120 mL ofdichloromethane was added dropwise, over a 10 min period, 5.04 g (30mmol) of 4-piperidino-piperidine (Aldrich, 90%) and 3.6 g (36 mmol) oftriethylamine in 30 mL of dichloromethane. A mildly exothermic reactionensued. After stirring 2 hours at room temperature, the orange solutionwas diluted with 100 mL of dichloromethane and washed with 10% sodiumbicarbonate solution (2×100 mL) and brine (1×100 mL). After drying oversodium sulfate, the solvent was removed at reduced pressure to afford10.7 g of crude product as a light tan solid (R_(f)=0.5, Silica, 10%MeOH/chloroform).

To this crude material was added 200 mL of 95% EtOH/5% MeOH followed by60 mL of hydrazine hydrate. The mixture was refluxed for 3 hours. Duringthe first 0.5 hour, the initially orange solution turned deep red-orangebefore turning orange again. After refluxing for 3 hours, most of thesolvent, water and hydrazine was removed at reduced pressure. To theresidue was added 50 mL of EtOH and solvent removed at reduced pressure.This was repeated 2 or more times to give a tan solid which was furtherdried in the vacuum oven to a constant weight of 13.5 g. To the flaskcontaining this solid was added 250 mL of water. Almost all of the solidwent into solution, then a fine light yellow precipitate formed. Afterstirring cooled in an ice bath for two hours, the solid was collected byvacuum filtration through a sintered glass filter, and rinsed with about20 mL of cold water. Drying in the vacuum oven at 40° C. overnightafforded 7.3 g (63% yield) of the title compound (PP-HOBT) as anoff-white crunchy powder, mp 195-200° C. (dec).

Example C-AA Synthesis of(S)-3-(L-Phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A: Synthesis of(S)-3-(N′-(tert-Butoxycarbonyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

To a solution of triethyl amine (519 μL, 3.8 mmol) and(S)-3-amino-5-phenyl-2-oxo-1,4-benzodiazepine (1.0 g, 3.8 mmol)(prepared according to the procedure of M. G. Bock et al., J. Org. Chem.1987, 52, 3232-3239) in 100 mL of anhydrous methylene chloride at −20°C. was added N-Boc-L-phenylglycine fluoride (Carpino et al, J. Org.Chem. 1991, 56, 2611-2614) in one portion. The reaction mixture wasstirred for 15 min. and quenched with saturated aqueous bicarbonate (10mL). The layers were separated, the organic layer washed sequentiallywith saturated aqueous bicarbonate, water and brine and then dried oversodium sulfate. Purification of the crude product using silica gelchromatography (10-50% ethyl acetate/hexane) gave 1.3 g (69%) of ahydroscopic white foam.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃): d=1.35 (br s, 9H), 3.41 (s, 3H), 5.30-5.45 (m,2H), 5.75-5.95 (m, 1H), 7.15-7.75 (m, 15H). IR (CDCl₃): 1709.7, 1676.6,1489, 1166.3 cm⁻¹. IEX MS (M+1): 498.0.

Step B: Synthesis of(S)-3-(L-Phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

(S)-3-(N′-(tert-Butoxycarbonyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(1.27 g, 2.55 mmol) was added to 50 mL of a stirring solution of 15% TFAin methylene chloride in one portion. After stirring 1 h, the reactionmixture was concentrated under reduced pressure and the residuedissolved in 100 mL of methylene chloride. This solution was washedtwice with saturated sodium bicarbonate, once with brine and then driedover sodium sulfate. Purification of the crude product using silica gelcolumn chromatography (5-10% methanol/methylene chloride) gave 743 mg(73%) of a very light green foam.

NMR data was as follows:

¹H NMR (CDCl₃): d=2.05 (br s, 1H), 3.45 (s, 3H), 5.51 (d, J=8.39 Hz,1H), 7.15-7.70 (m, 14H), 8.60 (d, J=830 Hz, 1H). IR (CDCl₃): 1673.3,1601.1, 1506.1 cm⁻¹. IEX MS (M+1): 399.2.

Example C-AB Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A: Synthesis of3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

To a solution of3-(Benzoxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one(Bock, M. G. et al, Tetrahedron Lett. 1987, 28, 939; 4.0 g, 10.4 mmol)in 40 mL of anhydrous DMF at 0° C. was added potassium tert-butoxide(1.51 g, 13.5 mmol) in one portion. The reaction mixture was stirred 20min. and α-broinoacetophenone (Lancaster; Windham, N.H.; 2.9 g, 14.6mmol) was added. The reaction mixture was warmed to room temperatureover 30 min. and then diluted with 100 mL of water and 200 mL ofmethylene chloride. The layers were separated. The organic layer wasextracted with water and dried over sodium sulfate. Purification of thecrude product by silica gel column chromatography (0-5% ethylacetate/methylene chloride) gave 4.2 g (81%) of an off white foam.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃): d=5.16 (s, 2H), 5.34 (s, 2H), 5.50 (d, J=8.33Hz, 1H), 6.70 (d, J=8.28 Hz, 1H), 7.20-7.70 (m, 12H), 7.91 (d, J=7.54Hz, 2H). IR (CHCl₃): 1706.04, 1685.3, 1505.9, 1489.1, 1450.3, 1244.7cm⁻¹. IEX MS (M+1): 504.3.

Step B: Synthesis of3-Amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

A solution of3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(3.7 g, 7.36 mmol) in 100 mL of anhydrous methylene chloride was cooledto 0° C. under nitrogen. A stream of anhydrous HBr gas was then bubbledthrough this solution for 1 h. The bubbler was removed and the reactionwas warmed to room temperature under nitrogen. After stirring 1 h thereaction was concentrated under vacuum and the residue was redissolvedin 20 mL of methylene chloride. The crude HBr salt of the product wasprecipitated from solution using 300 mL of anhydrous ether and collectedby filtration as a light yellow solid. After washing with ether, thesolid was dissolved in methylene chloride and saturated sodiumbicarbonate. The layers were separated and the organic layer wasextracted with saturated sodium bicarbonate. The combined aqueous layerswere then back extracted twice with methylene chloride. The combinedorganic layers were extracted once with water and dried over sodiumsulfate. After concentration under vacuum, 2.27 g of the product wasobtained as an orange foam which was carried on without furtherpurification.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃): d=2.60 (br s, 2H), 4.72 (s, 1H), 5.34 (s, 2H),7.10-7.70 (m, 12H), 7.91 (d, J=7.60 Hz, 2H). IEX MS (M+1): 370.2.

Step C: Synthesis of3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

To a solution of HOBt-H₂O (697 mg, 5.16 mmol), N,N-diisopropylethylamine(900 μL, 5.16 mmol) and N-t-BOC-L-alanine (975 mg, 5.16 mmol) in 20 mLof anhydrous THF at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI; 986 mg, 5.16 mmol) in one portion.After stirring 5 min., a solution of3-amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(2.0 g, 5.43 mmol) in 20 mL of anhydrous THF was added via syringe andthe reaction mixture was warmed to room temperature and stirredovernight. The reaction mixture was diluted with 200 mL methylenechloride, extracted sequentially with 10% citric acid, saturated sodiumbicarbonate, water and brine and then dried over sodium sulfate.Purification of the crude product using silica gel chromatography(10%-30% ethyl acetate/methylene chloride) gave 2.59 g (93%) of a whitefoam.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃): d=1.30-1.60 (m, 12H), 4.35 (br s, 1H),5.00-5.50 (m, 3H), 5.65-5.70 (m, 1H), 7.15-7.65 (m, 12H), 7.70-7.80 (m,1H), 7.85-7.95 (m, 1H). IR (CHCl₃): 1705.8, 1678.8, 1488.7, 1450.2,1230.4, 1164.4 cm¹. IEX MS (M+1): 541.2.

Step D: Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(2.5 g, 4.63 mmol) was added to 100 mL of a stirring solution of 15%TFA/methylene chloride in one portion. After stirring 2 h, the reactionmixture was concentrated under reduced pressure and the residue wasdissolved in 150 mL of methylene chloride. This solution was washedtwice with saturated sodium bicarbonate, once with brine and then driedover sodium sulfate. Purification of the crude product using silica gelcolumn chromatography (1-10% methanol/methylene chloride) gave 1.91 g(94%) of the title compound as a white foam.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃): d=1.30-1.50 (m, 3H), 1.80-2.20 (br s, 2H),3.55-3.75 (m, 1H), 5.20-5.45 (m, 2H), 5.67 (t, J=7.48 Hz, 1H), 7.20-7.65(m, 12H), 7.90 (d, J=7.7 Hz, 2H), 8.80 (dd, J₁=25.09 Hz, J₂=8.33 Hz,1H). EX MS (M+1): 441.2.

Example C-AC Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-(4,4,4trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A: Synthesis of3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

To a solution of3-(benzoxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one(3.7 g, 9.61 mmol) in 40 mL of anhydrous DMF at 0° C. was addedpotassium tert-butoxide (1.6 g, 14.4 mmol) in one portion. The reactionmixture was stirred 20 min. and 4,4,4-trifluoro-1-bromobutane(Lancaster; Windham, N.H.; 2.6 g, 13.4 mmol) was added. The reactionmixture was warmed to room temperature over 30 min. and then dilutedwith 100 mL of water and 200 mL of methylene chloride. The layers wereseparated. The organic layer was extracted with water and dried oversodium sulfate. Purification of the crude product by silica gel columnchromatography (0-3% ethyl acetate/methylene chloride) gave 1.52 g (32%)of an off white foam.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃): d=1.50-2.10 (m, 4H), 3.70-3.90 (m, 1H),4.354.55 (m, 1H), 5.15 (s, 2H), 5.33 (d, J=8.47 Hz, 1H), 6.67 (d, J=8.40Hz, 1H), 7.2-7.70 (m, 14H). IR (CHCl₃): 1720.4, 1683.0, 1604.8, 1505.5,1451.1, 1323.9, 1254.5, 1148.4 cm⁻¹. IEX MS (M+1): 496.3.

Step B: Synthesis of3-Amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

A solution of3-(benzoxycarbonyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(1.42 g, 2.87 mmol) in 50 mL of anhydrous methylene chloride was cooledto 0° C. under nitrogen. A stream of anhydrous HBr gas was slowlybubbled through the solution for 1 h. The bubbler was removed and thereaction was warmed to room temperature under nitrogen. After stirringfor 1 h, the reaction was concentrated under vacuum and the residue wasredissolved in 10 mL of methylene chloride. The crude HBr salt of theproduct was precipitated from solution using 90 mL of anhydrous etherand collected by filtration. After washing with ether, the HBr salt wasdissolved in methylene chloride and saturated sodium bicarbonate. Thelayers were separated and the organic layer was extracted with saturatedsodium bicarbonate. The combined aqueous layers were then back extractedtwice with methylene chloride. The combined organic layers wereextracted once with water and dried over sodium sulfate. Afterconcentration under vacuum, 1.06 g (100%) of the product was obtained asa white foam which was carried on without further purification.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃): d=1.60-2.10 (m, 4H), 2.76 (br s, 2H), 3.75-3.85(m, 1H), 4.40-4.60 (m, 2H), 7.20-7.70 (m, 9H). IEX MS (M+1): 362.1.

Step C: Synthesis of3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

To a solution of HOBt-H₂O (373 mg, 2.76 mmol), N,N-diisopropylethylamine(481 μL, 2.76 mmol) and N-t-BOC-L-alanine (522 mg, 2.76 mmol) in 10 mLof anhydrous THF at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI; 527 mg, 2.76 mmol) in one portion.After stirring 5 min., a solution of3-amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(1.05 g, 2.91 mmol) in 10 mL of anhydrous THF was added via syringe andthe reaction mixture was warmed to room temperature and stirredovernight. The reaction mixture was diluted with 100 mL methylenechloride, extracted sequentially with 10% citric acid, saturated sodiumbicarbonate, water and brine and then dried over sodium sulfate.Purification of the crude product using silica gel chromatography(10%-30% ethyl acetate/methylene chloride) gave 1.28 g (83%) of a whitefoam.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃): d=1.40-2.10 (m, 16H), 3.70-3.85 (m, 1H),4.304.55 (m, 2H), 5.10 (br s, 1H), 5.45-5.55 (m, 1H), 7.25-7.80 (m,10H). IR (CDCl₃): 1676.6, 1605.2, 1488.6, 1450.9, 1393.2, 1338.7,1324.9, 1253.8, 1150.4 cm⁻¹. IEX MS (M+1): 533.1.

Step D: Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(1.21 g, 2.27 mmol) was added to 50 mL of a stirring solution of 15%TFA/methylene chloride in one portion. After stirring 2 h, the reactionmixture was concentrated under reduced pressure and the residue wasdissolved in 100 mL of methylene chloride. This solution was washedtwice with saturated sodium bicarbonate, once with brine and then driedover sodium sulfate. Purification of the crude product using silica gelcolumn chromatography (1-5% methanol/methylene chloride) gave 670 mg(68%) of a light pink foam.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃): d=1.43 (t, J=7.0 Hz, 3H), 1.60-2.20 (m, 7H),3.60-3.85 (m, 2H), 4.35-4.55 (m, 1H), 5.51 (dd, J₁=8.36 Hz, J₂=2.48 Hz,1H), 7.20-7.70 (m, 9H), 8.80 (dd, J₁=27.73 Hz, J₂=8.34 Hz, 1H). IEX MS(M+1): 433.2.

Example C-AD Synthesis of3-(N′-(Chloroacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

A solution of3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(20.0 mg, 0.0595 mmol), a-chloroacetyl chloride (5.9 μL, 0.0744 mmol)and piperidinylmethyl polystyrene (59.5 mg, 3.6 mmol/g (Fluka)) in 1 mLof methylene chloride were shaken for 20 min. Aminomethyl polystyrene(58 mg, 3.0 mmol/g (Advanced Chemtech)) was then added and the reactionmixture was shaken for an additional 15 min. and filtered. Removal ofthe solvent under reduced pressure provided 23.9 mg (98%) of the crudeproduct which was used without further purification.

NMR data was as follows:

¹H NMR (300 MHz, CDCl₃): d=1.40-1.60 (m, 3H), 3.40-3.6 (m, 3H), 4.1 (s,2H), 4.604.80 (m, 1H), 5.45-5.50 (m, 1H), 7.20-7.90 (m, 11H).

Example C-AE Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Step A: Synthesis of3-Amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

The title compound was synthesized as described in Synth. Commun.,26(4), 721-727 (1996).

Step B: Synthesis of3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

A solution of L-Boc-alanine (1.74 g, 9.20 mmol), HOBt monohydrate (1.24g, 9.20 mmol), diisopropylethylamime (1.6 mL, 9.20 mmol) and CHCl₂ (30mL) was purged with nitrogen and cooled in an ice bath. To the coldsolution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.76 g, 9.20 mmol) followed by a solution of3-amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(2.45 g, 9.20 mmol) dissolved in CH₂Cl₂ (15 mL). The cold bath wasremoved and the solution stirred overnight at room temperature. Thereaction mixture was extracted with H₂O, 0.1 N aq. citric acid, 5% aq.NaHCO₃, and brine. The remaining CH₂Cl₂ solution was dried (MgSO₄) andconcentrated to a tan foam. The title compound was crystallized fromCH₂Cl₂/EtOAc to give 3.47 g (86% yield) of white crystals, mp. 228-229°C.

Anal. Calcd for C₂₃H₂₇N₅O₄: C, 63.14; H, 6.22; N, 16.01. Found: C,63.25; H, 6.15; N, 15.95. MS (FD⁺) 437 m/z.

Step C: Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

A solution of3-[(N-tert-butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(3.42 g, 7.82 mmol) in CH₂Cl₂ (90 mL) was cooled in an ice bath andtreated with TFA (13.2 mL, 172 mmol). The cold bath was removed and thesolution stirred at room temperature for four hours. The reactionmixture was washed with 1 M aq. K₂CO₃ and the aqueous back-extractedwith CH₂Cl₂. The combined extracts were washed with H₂O, dried (MgSO₄)and concentrated to obtain 1.75 g (66% yield) of the title compound asan off-white foam. MS (IS⁺) 338 (m/e).

¹H NMR (CDCl₃): d=8.76-8.86 (1H, m), 8.63 (1H, m), 8.17 (1H, m), 7.82(2H, m), 7.60 (1H, m), 7.41 (3H, m), 5.60 (1H, m), 3.63 (1H, m), 3.49(3H, s), 1.66 (2H, broad), 1.45 (3H, m).

Example C-AF Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Step A: Synthesis of3-Amino-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

The title compound was synthesized as described in Synth. Commun.,26(4), 721-727 (1996).

Step B: Synthesis of3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

A solution of L-Boc-alanine (1.80 g, 9.50 mmol), HOBt monohydrate (1.28g, 9.50 mmol), diisopropylethylamime (1.65 mL, 9.50 mmol) and CH₂Cl₂ (40mL) was purged with nitrogen and cooled in an ice bath. To the coldsolution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.82 g, 9.50 mmol) followed by a solution of3-amino-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(3.34 g, 9.50 mmol) dissolved in CH₂Cl₂ (25 mL). The cold bath wasremoved and the solution stirred overnight at room temperature. Thereaction mixture was extracted with H₂O, 5% aq. NaHCO₃, and brine. Theremaining CH₂Cl₂ solution was dried (MgSO₄) and concentrated to a tanfoam. The title compound was isolated via column chromatography (2%MeOH/CH₂Cl₂ to 10% MeOH/CH₂Cl₂) to give 3.53 g (71% yield) of yellowfoam.

MS (FD⁺) 522 (m/z).

¹H NMR (CDCl₃): d=8.62 (1H, d), 8.11 (1H, m), 7.80 (2H, m), 7.59 (2H,m), 7.32-7.45 (2H, m), 5.54 (1H, m), 5.02-5.18 (1H, m), 4.38 (1H, m),4.20 (1H, m), 3.83 (1H, m), 2.62 (2H, t), 2.44 (4H, m), 1.40-1.56 (12H,m), 0.88 (6H, m).

Step C: Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

The title compound was synthesized using the procedure described inExample C-AE, Step C. A solution of3-[(N-tert-butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(3.52 g, 6.73 mmol) was treated with TFA (11.4 mL, 148 mmol) to give2.61 g (92% yield) the title compound as a light yellow foam.

MS (IS⁺) 423 (m/e).

¹H NMR (CDCl₃): d=8.78-8.93 (1H, m), 8.62 (1H,d), 8.11 (1H, m), 7.80(2H, m), 7.58 (2H, m), 7.39 (2H, m), 5.58 (1H, m), 4.22 (1H, m), 3.88(1H, m), 3.61 (1H, m), 2.67 (2H, t), 2.49 (4H, m), 1.73 (2H, broad),1.42 (3H, m), 0.91 (6H, m).

Example C-AG Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Step A: Synthesis of3-Amino-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

The title compound was synthesized as described in Synth. Commun.,26(4), 721-727 (1996).

Step B: Synthesis of3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

A solution of L-Boc-alanine (1.57 g, 8.33 mmol), HOBt monohydrate (1.13g, 8.33 mmol), diisopropylethylamime (1.45 mL, 8.33 mmol) and CH₂Cl₂ (40mL) was purged with nitrogen and cooled in an ice bath. To the coldsolution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.60 g, 8.33 mmol) followed by a solution of3-amino-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(2.92 g, 8.33 mmol) dissolved in CH₂Cl₂ (25 mL). The cold bath wasremoved and the solution stirred overnight at room temperature. Thereaction mixture was extracted with H₂O, 0.1 N aq. citric acid, 5% aq.NaHCO, and brine. The remaining CH₂Cl₂ solution was dried (MgSO₄) andconcentrated to a yellow foam. The title compound was isolated viacolumn chromatography (20% EtOAc/hexanes to 60% EtOAc/hexanes) to give4.19 g (96% yield) of light yellow foam.

MS (FD⁺) 521 (m/z).

¹H NMR (CDCl₃): d=8.65 (1H, t), 8.17 (1H, t), 7.90 (1H, t), 7.71-7.85(1H, m), 7.54 (1H, m), 7.44 (1H, t), 7.37 (1H, d), 7.24-7.32 (1H, m),7.14 (1H, m), 5.67 (1H, dd), 5.18 (1H, broad), 4.93-5.07 (1H, m),4.50-4.64 (1H, m), 4.38 (1H, broad), 1.42-1.51 (12H, m), 1.26 (9H, d).

Step C: Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

The title compound was synthesized using the procedure described inExample C-AE, Step C. A solution of3-[(N-tert-butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(4.18 g, 8.01 mmol) was treated with TFA (13.6 mL, 176 mmol) to give3.14 g (93% yield) the title compound as an off-white foam.

MS (IS⁺) 422 (m/e).

¹H NMR (CDCl₃) d=8.85-8.99 (1H, m), 8.68 (1H, d), 8.20 (1H, t), 7.87(1H, t), 7.58 (1H, t), 7.42 (2H, m), 7.30 (1H, t), 7.17 (1H, d), 5.72(1H, m), 5.08 (1H, d), 4.60 (1H, d), 3.66 (1H, m), 1.47 (3H, m), 1.28(9H, m).

Example C-AH Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one

Step A: Synthesis of3-Amino-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one

The title compound was synthesized in a manner similar to the proceduredescribed in Synth. Commun., 26(4), 721-727 (1996), starting with2-(2-aminobenzoyl)thiazole (prepared as described in Tetrahedron, 51(3),773-786, (1995)).

MS (IS⁺) 273 (m/e).

¹H NMR (CDCl₃): d=7.83-7.94 (2H, m), 7.61 (1H, t), 7.50 (1H, d), 7.34(2H, m), 4.60 (1H, s), 3.46 (3H, s), 1.97 (2H, broad).

Step B: Synthesis of3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one

A solution of L-Boc-alanine (1.85 g, 9.77 mmol), HOBt monohydrate (1.32g, 9.77 mmol), diisopropylethylamime (1.70 mL, 9.77 mmol) and CH₂Cl₂ (30mL) was purged with nitrogen and cooled in an ice bath. To the coldsolution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.87 g, 9.77 mmol) followed by a solution of3-amino-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one(2.66 g, 9.77 mmol) dissolved in CH₂Cl₂ (20 mL). The cold bath wasremoved and the solution stirred overnight at room temperature. Thereaction mixture was extracted with H₂O, 0.1 N aq. citric acid, 5% aq.NaHCO₃, and brine. The remaining CH₂Cl₂ solution was dried (MgSO₄) andconcentrated to a light yellow foam. The title compound was crystallizedfrom EtOAc/hexane to give 3.22 g (74% yield) of white crystals, mp.196-197° C.

Anal. Calcd for C₂₁H₂₅N₅O₄S: C, 56.87; H, 5.68; N, 15.79. Found: C,56.74; H, 5.75; N, 15.55. MS (IS⁺) 444 m/e.

Step C: Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one

The title compound was synthesized using the procedure described inExample C-AE, Step C.

Example C-AI Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(thiophen-2-yl)-1H-1,4-benzodiazepin-2-one

Step A: Synthesis of3-Amino-2,3-dihydro-1-methyl-5-(2-thiophen-2-yl)-1H-1,4-benzodiazepin-2-one

The title compound was synthesized in a manner similar to the proceduredescribed in Synth. Commun., 26(4), 721-727 (1996), starting with2-(2-aminobenzoyl)thiophene (prepared as described in Collect. Czech.Chem. Commun., 34(2), 468-478, (1969)).

MS (IS⁺) 272 (m/e).

¹H NMR (CDCl₃): d=7.68 (1H, d), 7.60 (1H, t), 7.48 (1H, m), 7.35 (2H,d), 7.28 (1H, m), 7.15 (1H, d), 7.05 (1H, d), 4.50 (1H, broad), 3.45(3H, s), 2.26 (2H, broad).

Step B: Synthesis of3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiophenyl)-1H-1,4-benzodiazepin-2-one

The title compound was synthesized in a manner similar to the proceduredescribed in Example C-AH, Step B.

MS (IS⁺) 443 (m/e).

¹H NMR (CDCl₃): d=7.69 (1H, d), 7.61 (2H, m), 7.48 (1H, d), 7.27-7.42(2H, m), 7.18 (1H, m), 7.05 (1H, m), 5.51 (1H, d), 5.13 (1H, broad),4.36 (1H, broad), 3.44 (3H, s), 1.38-1.57 (12H, m).

Step C: Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiophenyl)-1H-1,4-benzodiazepin-2-one

The title compound was synthesized in a manner similar to the proceduredescribed in Example C-AE, Step C.

MS (IS⁺) 343 (m/e).

¹H NMR (CDCl₃): d=8.55 (1H, d), 7.68 (1H, d), 7.59 (1H, m), 7.48 (1H,d), 7.36 (1H, d), 7.31 (1H, d), 7.16 (1H, m), 7.04 (1H, t), 5.54 (1H,d), 3.58 (1H, m), 3.45 (3H, s), 1.41 (3H, d).

Additionally, the following procedures provide various carboxylic acidesters which can be hydrolyzed using General Procedures AC or BD belowto afford the corresponding carboxylic acids. Coupling of the resultingcarboxylic acids to the amines employed above using the GeneralProcedures set forth above provides for additional compounds within thescope of this invention.

General Procedure AA Reductive Amination

To a solution of the arylamine in ethanol in a hydrogenation flask wasadded 1 equivalent of the 2-oxocarboxylic acid ester (e.g., pyruvateester), followed by 10% palladium on carbon (25 weight percent based onthe arylamine). The reaction was hydrogenated at 20 psi H₂ on a Parrshaker until complete reaction was indicated by tlc (30 minutes to 16hours). The reaction mixture was then filtered through a pad of Celite545 (available from Aldrich Chemical Company, Inc.) and stripped free ofsolvent on a rotary evaporator. The crude product residue was thenfurther purified via chromatography.

General Procedure AB First Transesterification Technique

A solution of 1-5 equivalents of the desired alcohol was added to 1equivalent of sodium hydride in toluene. After off-gassing had ceased,the compound to be transesterified, dissolved in toluene, was added.After 0.5 hours, the reaction was either heated to 40° C. and placedunder house vacuum (20 mmHg), or nitrogen was bubbled through thesolution while it was heated at 90° C. The reaction was followed by tlc,and when the reaction was complete the solution was cooled and quenchedwith water or 1M HCl, and in smaller scale reactions diluted with ethylacetate. The organic phase was extracted with saturated aqueous NaHCO₃,then washed with saturated aqueous NaCl and dried over MgSO₄. Thesolution was stripped free of solvent on a rotary evaporator, and thecrude product residue was then further purified by chromatography.Alternatively, the reaction mixture was worked-up by evaporation of thesolvents and direct chromatography of the crude mixture.

This procedure is particularly useful in the case of costly and/or highboiling alcohols.

General Procedure AC Second Transesterification Technique

The compound to be transesterified was placed in a large excess of thedesired alcohol. A catalytic amount of dry NaH was added, and thereaction was followed by tlc until the presence of starting material wasno longer detected. The reaction was quenched with a few milliliters of1N HCl, and after a few minutes of stirring saturated aqueous NaHCO₃ wasadded. The organic phase was washed with saturated aqueous NaCl anddried over MgSO₄. The solution was stripped free of solvent on a rotaryevaporator, and the crude product residue was then further purified bychromatography.

General Procedure AD Third Transesterification Technique

The compound to be transesterified was placed in a large excess of thedesired alcohol. A catalytic amount of dry NaH was added, and thereaction was followed by tic until the presence of starting material wasno longer detected. The reaction was quenched with a few milliliters of1N HCl, and after a few minutes of stirring saturated aqueous NaHCO₃ wasadded. The volume of the reaction mixture was reduced on a rotaryevaporator until the excess alcohol was removed and then the remainingresidue was taken up in ethyl acetate and additional water was added.The organic phase was washed with saturated aqueous NaCl and dried overMgSO₄. The solution was stripped free of solvent on a rotary evaporator,and the crude product residue was then further purified bychromatography.

This procedure is particularly employed in the case of low boiling,inexpensive alcohols, miscible with water.

General Procedure AE O-Alkylation Technique

To a carboxylic acid compound (prepared, for example, by reductiveamination via General Procedure AA to provide for the N-aryl amino acidester, followed by hydrolysis via Procedure AF) in DMF was added 1.5equivalents K₂CO₃, followed by 1 equivalent of alkylating agent (e.g.,tert-butyl bromoacetate). The reaction was stirred at room temperaturefor 2 hours, then was quenched with water and extracted into ethylacetate. The organic phase was washed with saturated aqueous NaHCO₃,water, and saturated aqueous NaCl, and was then dried over MgSO₄. Thesolution was stripped free of solvent on a rotary evaporator to yieldthe crude product.

General Procedure AF Ester Hydrolysis to Free Acid

To a carboxylic ester compound (prepared, for example, by reductiveamination via General Procedure AA to provide for the N-aryl amino acidester) in a 1:1 mixture of CH₃OH/H₂O was added 2-5 equivalents of K₂CO₃.The mixture was heated to 50° C. for 0.5 to 1.5 hours until tlc showedcomplete reaction. The reaction was cooled to room temperature and themethanol was removed on a rotary evaporator. The pH of the remainingaqueous solution was adjusted to ˜2, and ethyl acetate was added toextract the product. The organic phase was then washed with saturatedaqueous NaCl and dried over MgSO₄. The solution was stripped free ofsolvent on a rotary evaporator to yield the crude product.

General Procedure AG N-Heteroarylation of Alanine

A solution of 1.1 equivalents of L-alanine and 2 equivalents NaOH inDMSO was stirred at room temperature for 1 hour, then 1 equivalent of2-chlorobenzothiazole was added. The mixture was heated to 100° C. for 4hours, then cooled to room temperature and poured onto ice. The pH ofthe resulting aqueous solution was adjusted to ˜2, and the precipitatedsolid was removed by filtration. This solid was then dissolved in 1NNaOH and the resulting solution was filtered through a pad of Celite545. The pH of the filtrate was adjusted to ˜2, and the whiteprecipitate was removed by filtration and washed with water to yield thecrude product.

General Procedure AH EDC Coupling

To a 1:1 mixture of the desired acid and alcohol in CH₂Cl₂ at 0° C. wasadded 1.5 equivalents triethylamine, followed by 2.0 equivalentshydroxybenzotriazole monohydrate, then 1.25 equivalents ofethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (EDC). The reactionwas stirred overnight at room temperature, then transferred to aseparatory funnel and washed with water, saturated aqueous NaHCO₃, 1NHCl, and saturated aqueous NaCl, and was then dried over MgSO₄. Thesolution was stripped free of solvent on a rotary evaporator to yieldthe crude product.

General Procedure Al Oxime or Amine Coupling Technique

The trichlorophenyl ester (1 eq) of a carboxylic acid was stirred in DMFor THF. The oxime or amine (1.2 eq) was added and the mixture wasstirred at ambient temperature for 14 hours. In cases where thehydrochloride salt form of an amine was used, a suitable base such asN,N-diisopropylethylamine (1.2 eq) was also added. The resulting mixturewas concentrated under reduced pressure to yield a crude product whichwas used without purification or was purified by silica gelchromatography and/or crystallization.

General Procedure AJ Alkylation Technique

The amine (1 eq), the α-bromo ester (1.1 eq) and a suitable base (suchas triethylamine) (2 eq) were stirred in chloroform. The resultingsolution was heated at reflux for 4-12 hours. After cooling, the mixturewas diluted with chloroform and washed with water. The organic portionwas dried (sodium sulfate) and concentrated under reduced pressure. Thecrude product was purified by silica gel chromatography.

General Procedure AK Oxime or Alcohol Coupling Technique

The carboxylic acid (1 eq) was stirred in a suitable solvent (such asTHF, dioxane or DMF). An alcohol or oxime (1-5 eq) was added. EDChydrochloride (1.2 eq) and hydroxybenzotriazole hydrate (1 eq) wereadded. A suitable base (such as 4-methylmorpholine or triethylamine)(0-1 eq) was added. A catalytic amount (0.1 eq) of4-dimethylaminopyridine was added. The mixture was stirred at ambienttemperature and under a dry atmosphere of nitrogen. After 20 hours, themixture was concentrated under reduced pressure. The resultingconcentrate was partitioned between ethyl acetate and water. The organicportion was separated and washed with aqueous sodium bicarbonate andbrine. The organic portion was dried (sodium sulfate) and concentratedunder reduced pressure. The crude product was used without purificationor was purified by silica gel chromatography and/or crystallization.

General Procedure AL EDC Coupling

The carboxylic acid was dissolved in methylene chloride. The amino acid(1 eq.), N-methylmorpholine (5 eq.) and hydroxybenzotriazole monohydrate(1.2 eq.) were added in sequence. A cooling bath was applied to theround bottomed flask until the solution reached 0° C. At that time, 1.2eq. of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)was added. The solution was allowed to stir overnight and come to roomtemperature under nitrogen pressure. The reaction mixture was worked upby washing the organic phase with saturated aqueous sodium carbonate,0.1M citric acid, and brine before drying with sodium sulfate. Thesolvents were then removed to yield crude product. Pure products wereobtained by flash chromatography in an appropriate solvent.

General Procedure AM Triflate Displacement

To a 0° C. solution of iso-butyl R-(+)-lactate in CH₂Cl₂ was added 1.1equivalents of trifluoromethanesulfonic anhydride. After stirring atroom temperature for 20 min, 1.1 equivalents of 2,6-lutidine was addedand stirring was continued for 10 min. This solution was thentransferred to a flask containing 1 equivalent the arylamine and 1equivalent N,N-diisopropylethylamine in CH₂Cl₂ or CH₃NO₂ at 0° C. Thereaction was held overnight at room temperature and then stripped freeof solvent on a rotary evaporator. The residue was dissolved in ethylacetate, washed with 5% citric acid, followed by saturated aqueous NaCl,dried over magnesium sulfate or sodium sulfate and then the solution wasstripped free of solvent on a rotary evaporator to yield the crudeproduct, which was then purified by chromatography.

General Procedure AN BOC Removal

The BOC-protected compound was added to a 1:1 mixture of CH₂Cl₂ andtrifluoroacetic acid, and was stirred until tlc indicated completeconversion, typically 2h. The solution was then stripped to dryness andthe residue was taken up in ethyl acetate and extracted with dilute HCl.The acid reaction was neutralized and extracted with ethyl acetate. Theorganic phase was washed with saturated aqueous NaCl and dried overMgSO₄. The solution was stripped free of solvent on a rotary evaporatorto yield the product.

General Procedure AO Synthesis of Pyruvate Esters

To a mixture of pyruvic acid (8.8 g, 0.1 mol) (Aldrich) in 100 mL ofbenzene was added iso-butanol (14.82 g, 0.2 mol) and a catalytic amountof p-toluenesulfonic acid. The mixture was then refluxed using a DeanStark apparatus. After 4 hours, the reaction appeared to be completewith the isolation of 1.8 g (0.1 mol) of water. The benzene andiso-butanol were removed on a rotary evaporator. The residue (14 g, 0.1mol), which was primarily the pyruvate iso-butyl ester by nmr [¹H-Nmr(CDCl₃): =4.0 (d, 2H), 2.5 (s, 3H), 2.0 (m, 1H), 1.0 (d, 6H)], was usedwithout further purification. By substituting other alcohols in place ofiso-butanol (e.g., ethanol, isopropanol, n-butanol, benzyl alcohol andthe like), other esters of pyruvic acid can be prepared in a similarmanner.

General Procedure AP Aromatic Nucleophilic Substitution ofFluorobenzenes

A mixture of 1.82 g (10 mmol) of D,L-alanine iso-butyl esterhydrochloride, the fluorobenzene (10 mmol) and 3 g of anhydrouspotassium carbonate in 10 mL of DMSO was stirred at 120° C. for 2-5hours. The reaction mixture was then cooled to room temperature anddiluted with 100 mL of ethyl acetate. The ethyl acetate extract waswashed with water (3×), dried over MgSO₄ and evaporated to dryness toafford the crude product, which was further purified by columnchromatography.

General Procedure AQ Fourth Transesterification Technique

The ester to be transesterified was dissolved in a large excess of thealcohol and 0.3 equivalents of titanium(IV) isopropoxide (Aldrich) wasadded. The reaction was followed by tlc until complete and then thevolatiles were removed at reduced pressure. The resulting crude materialwas then chromatographed to obtain the desired product.

General Procedure AR Synthesis on N-BOC Anilines

To a solution of the aniline in THF was added dropwise 1 equivalent ofdi-tert-butyl dicarbonate (Aldrich) in THF and then 1.5 equivalents of10N aqueous sodium hydroxide at 0° C. After stirring at room temperaturefor 16 hours, or heating at 80° C. for 3 hours, if needed, the reactionmixture was diluted with ether and washed with NaHCO₃, brine, dried oversodium sulfate and potassium carbonate, concentrated at reduced pressureand chromatographed to afford the N-BOC aniline.

General Procedure AS Oxime Ester Formation

The trichlorophenyl ester (1 eq.) was stirred in DMF or THF. The oxime(1.2 eq.) was added and the mixture was stirred at ambient temperaturefor 1 to 4 hours. The resulting mixture was concentrated under reducedpressure and the residue was purified by silica gel chromatographyand/or crystallization.

Example AA Synthesis of D,L-Alanine iso-Butyl Ester Hydrochloride

A mixture of 35.64 g (0.4 mol) of D,L-alanine (Aldrich), 44 mL (0.6 mol)of thionyl chloride (Aldrich) and 200 mL of iso-butanol was refluxed for1.5 hours. The volatiles were removed at reduced pressure at 90° C.under reduced pressure to give the title compound as an oil, which wasused without further purification.

NMR data was as follows:

¹H-NMR (CDCl₃): d=8.72 (br s, 3H), 4.27 (q, J=7.4 Hz, 1H), 3.95 (m, 2H),1.96 (s, 1H), 1.73 (d, J=7.2 Hz, 3H), 0.92 (d, J=6.7 Hz, 6H). ¹³C-nmr(CDCl₃): d=170.0, 72.2, 49.2, 27.5, 18.9, 16.1.

General Procedure BA Coupling of Acid Halides With H₂NCH(R²)C(O)XR³

To a stirred solution of (D,L)-alanine iso-butyl ester hydrochloride(from Example BB below) (4.6 mmol) in 5 mL of pyridine is added 4.6 mmolof an acid chloride. Following precipitation of the pyridiniumhydrochloride, the mixture is stirred for 3.5 h, diluted with 100 mL ofdiethyl ether, washed with 10% HCl three times, brine once, 20%potassium carbonate once and brine once. The solution was dried overmagnesium sulfate, filtered, and evaporated at reduced pressure to yieldthe product. Other amino acid esters may also be employed in thisprocedure.

General Procedure BB Coupling of R¹C(X′)(X″)C(O)OH With H₂NCH(R²)C(O)XR³

A solution of the acid (3.3 mmol) and CDI in 20 mL THF was stirred for 2h. L-alanine iso-butyl ester hydrochloride (from Example BB below) (3.6mmol) was added, followed by 1.5 mL (10.8 mmol) of triethylamine. Thereaction mixture was stirred overnight. The reaction mixture was dilutedwith 100 mL of diethyl ether, washed with 10% HCl three times, brineonce, 20% potassium carbonate once and brine once. The solution wasdried over magnesium sulfate, filtered, and evaporated at reducedpressure to yield the product. Other amino acid esters may also beemployed in this procedure.

General Procedure BC Esterification of R¹C(X′)(X″)C(O)NHCH(R²)C(O)OHWith HOR³

CDI is added to a stirred solution of an N-acyl amino acid, and themixture is stirred for about 1.5 h. An alcohol is added the mixture,followed by addition of an equivalent of NaH. Bubbling should occurimmediately to evolve the generated hydrogen gas. The reaction mixtureis stirred overnight, diluted with diethyl ether, washed with 10% HClthree times, brine once, 20% potassium carbonate once and brine once.The solution is then dried over magnesium sulfate, filtered, andevaporated at reduced pressure to yield the product.

General Procedure BD Ester Hydrolysis to the Free Acid

Ester hydrolysis to the free acid was conducted by conventional methods.Below are two examples of such conventional de-esterification methods.

To the ester in a 1:1 mixture of CH₃OH/H₂O was added 2-5 equivalents ofK₂CO₃. The mixture was heated to about 50° C. for about 0.5 to 1.5 hoursuntil tlc showed complete reaction. The reaction was cooled to roomtemperature and the methanol was removed at reduced pressure. The pH ofthe remaining aqueous solution was adjusted to about 2, and ethylacetate was added to extract the product. The organic phase was thenwashed with saturated aqueous NaCl and dried over MgSO₄. The solutionwas stripped free of solvent at reduced pressure to yield the product.

The amino acid ester was dissolved in dioxane/water (4:1) to which wasadded LiOH (˜2 eq.) that was dissolved in water such that the totalsolvent after addition was about 2:1 dioxane:water. The reaction mixturewas stirred until reaction completion and the dioxane was removed underreduced pressure. The residue was diluted with EtOAc, the layers wereseparated and the aqueous layer acidified to pH 2. The aqueous layer wasback extracted with EtOAc, the combined organics were dried over Na₂SO₄and the solvent was removed under reduced pressure after filtration. Theresidue was purified by conventional methods (e.g., recrystallization).

The following exemplifies this later example. The methyl ester of 3-NO₂phenylacetyl alanine 9.27 g (0.0348 mols) was dissolved in 60 mL dioxaneand 15 mL of H₂O and adding LiOH (3.06 g, 0.0731 mol) that has beendissolved in 15 mL of H₂O. After stirring for 4 hours, the dioxane wasremoved under reduced pressure and the residue diluted with EtOAc, thelayers were separated and the aqueous layer acidified to pH 2. Theaqueous layer was back extracted with EtOAc (4×100 mL), the combinedorganics were dried over Na₂SO₄ and the solvent was removed underreduced pressure after filtration. The residue was recrystallized fromEtOAc/isooctane giving 7.5 g (85%) of 3-nitrophenylacetyl alanine.C₁₁H₁₂N₂O₅ requires C=52.38, H=4.80, and N=11.11. Analysis foundC=52.54, H=4.85, and N=11.08. [ ]₂₃=−29.9 @ 589 nm.

General Procedure BE Low Temperature BOP Coupling of Acid and Alcohol

A solution of methylene chloride containing the carboxylic acid (100 M%)and N-methyl morpholine (150 M%) was cooled to −20° C. under nitrogen.BOP (105 M%) was added in one portion and the reaction mixture wasmaintained at −20° C. for 15 minutes. The corresponding alcohol (120 M%)was added and the reaction mixture was allowed to warm to roomtemperature and stirred for 12 hours. The reaction mixture was thenpoured into water and extracted with ethyl acetate (3×). The combinedethyl acetate portions were backwashed with saturated aqueous citricacid (2×), saturated aqueous sodium bicarbonate (2×), brine (1×), driedover anhydrous magnesium sulfate or sodium sulfate and the solventremoved under reduced pressure to yield the crude product.

General Procedure BF EDC Coupling of Acid and Amine

The acid derivative was dissolved in methylene chloride. The amine (1eq.), N-methylmorpholine (5 eq.), and hydroxybenzotriazole monohydrate(1.2 eq.) were added in sequence. The reaction was cooled to about 0° C.and then 1.2 eq. of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride was added. The solution was allowed to stir overnight andcome to room temperature under N₂ pressure. The reaction mixture wasworked up by washing the solution with saturated, aqueous Na₂CO₃, 0.1Mcitric acid, and brine before drying with Na₂SO₄ and removal of solventsto yield crude product. Pure products were obtained by flashchromatography in an appropriate solvent.

General Procedure BG

EDC Coupling of Acid and Amine A round bottom flask was charged withcarboxylic acid (1.0 eq.), hydroxy-benzotriazole hydrate (1. 1 eq.) andamine (1.0 eq.) in THF under nitrogen atmosphere. An appropriate amount(1.1 eq. for free amines and 2.2 eq. for hydrochloride amine salts) ofbase, such as Hunig's base was added to the well stirred mixturefollowed by EDC (1.1 eq.). After stirring from 4 to 17 hours at roomtemperature the solvent was removed at reduced pressure, the residuetaken up in EtOAc (or similar solvent)/water. The organic layer waswashed with saturated aqueous sodium bicarbonate solution, 1N HCl, brineand dried over anhydrous sodium sulfate. In some cases, the isolatedproduct was analytically pure at this stage while, in other cases,purification via chromatography and/or recrystallization was requiredprior to biological evaluation.

General Procedure BH Coupling of R¹C(X′)(X″)C(O)Cl with H₂NCH(R²)C(O)XR³

An excess of oxalyl chloride in dichloromethane was added to the acidderivative together with one drop of DMF. The resulting mixture wasstirred for about 2 hours or until bubbling ceases. The solvent was thenremoved under reduced pressure and rediluted with dry methylenechloride. To the resulting solution was added about 1.1 eq. of theappropriate amino acid ester and triethylamine (1.1 eq. in methylenechloride). The system was stirred at room temperature for 2 hours andthen the solvent was removed under reduced pressure. The residue wasdissolved in ethyl acetate, washed with 1N HCl followed by 1N NaOH. Theorganic layer was dried over anhydrous sodium sulfate, filtered and thesolvent removed under reduced pressure to provide for the desiredproduct.

General Procedure BI P-EPC coupling

P-EPC coupling employs an amino acid ester and a substituted acetic acidcompound. The acetic acid derivative is well known in the art and istypically commercially available. The amino acid ester is prepared byconventional methods from the known and typically commercially availableN-BOC amino acid as described in General Procedure BJ below.

Specifically, the appropriate amino ester free base (0.0346 mmols) andsubstituted phenylacetic acid (0.069 mmols) were dissolved in 2.0 mLCHCl₃ (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and thereaction was mixed for 4 days at 23 C. The reaction was filtered througha plug of cotton, rinsed with 2.0 mL of CHCl₃ and the filtrateevaporated under a stream of nitrogen. The purity of each sample wasdetermined by ¹H NMR and ranged from 50% to >95%. Between 8.0 and 15.0mg of final product was obtained from each reaction and was testedwithout additional purification.

General Procedure BJ Synthesis of Amino Acid Esters From theCorresponding N-BOC Amino Acid

A. Esterification of the Acid.

The N-BOC amino acid was dissolved in dioxane and treated with an excessof alcohol (˜1.5 eq.) and catalytic DMAP (100 mg) at 0° C. Stirring wascontinued until reaction completion whereupon the product was recoveredby conventional methods.

B. Removal of N-BOC Group.

The N-BOC protected amino acid was dissolved in methylene chloride(0.05M) and treated with 10 eq. of TFA at room temperature under anitrogen atmosphere. The reaction was monitored by tlc until startingmaterial was consumed usually within 1-5 hours. An additional 10 eq. ofTFA was added to the reaction if the starting material was still presentafter 5 hours. The reaction was carefully neutralized with Na₂CO₃,separated, the organic layer washed with brine and dried over anhydrousNa₂SO₄. The crude amine was then used without purification.

Specific exemplification of these procedures are as follows:

1. Racemic (+/−)-N-BOC-α-amino butyric acid (Aldrich) (9.29 g, 0.0457mol) was dissolved in 100 mL of dioxane and treated with iso-butylalcohol (6.26 mL, 0.0686 mol), EDC (8.72 g, 0.0457) and catalytic DMAP(100 mg) at 0° C. After stirring for 17 hours, the organics wereevaporated at reduced pressure, the residue diluted with EtOAc washedwith NaHCO₃, brine and dried over Na₂SO₄. Evaporation yields 8.42 g(71%) of an oil. C₁₃H₂₅NO₄ requires: C=60.21, H=9.72, and N=5.40. Analfound: C=59.91, H=9.89, and N=5.67.

The above N-BOC amino acid ester (8.00 g, 0.032 mol) was deprotected asabove giving 3.12 g (61%) of the free base as a colorless oil whichsolidifies upon standing.

2. L-N-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) was dissolved in 100 mLof CH₂Cl₂, iso-butyl alcohol (21.9 mL, 0.238 mol) and treated with DMAP(100 mg) and EDC (10.0 g, 0.52 mol) at O C. The mixture was stirred for17 hours, diluted with H₂O, washed with 1.0 N HCl, NaHCO₃, then brineand the organics were dried over Na₂SO₄. Filtration and evaporationyields 11.8 g (quantitative) of L-N-BOC alanine iso-butyl ester which iscontaminated with a small amount of solvent. A sample was vacuum driedfor analytical analysis.

C₁₂H₂₃NO₄ requires: C=58.79, H=9.38, and N=5.71. Anal found: C=58.73,H=9.55, and N=5.96.

The above N-BOC amino acid ester (11.8 g, 0.0481 mol) was deprotected asabove. The free base was converted to the corresponding HCl salt usingsaturated HCl (g)/EtOAc to give L-N-alanine iso-butyl esterhydrochloride. Obtained 4.2 g (48%) of a colorless solid. Anal. Calc.for C₇H₁₅NO₂.HCl: C=46.28, H=8.88, and N=7.71. Found: C=46.01, H=8.85,and N=7.68.

General Procedure BK Methyl Ester Formation From Amino Acids

The amino acid (amino acid or amino acid hydrochloride) is suspended inmethanol and chilled to 0° C. HCl gas is bubbled through this solutionfor 5 minutes. The reaction is allowed to warm to room temperature thenstirred for 4 hours. The solvents are then removed at reduced pressureto afford the desired amino acid methyl ester hydrochloride. Thisproduct is usually used without further purification.

Example BA Synthesis of Free and Polymer Bound PEPC

N-Ethyl-N′-3-(1-pyrrolidinyl)1propylurea

To a solution of 27.7 g (0.39 mol) ethyl isocyanate in 250 mL chloroformwas added 50 g (0.39 mol) 3-(1-pyrrolidinyl)propylamine dropwise withcooling. Once the addition was complete, the cooling bath was removedand the reaction mixture stirred at room temperature for 4 hours. Thereaction mixture was then concentrated under reduced pressure to give74.5 g (96.4%) of the desired urea as a clear oil.

1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC)

To a solution of 31.0 g (0.156 mol)N-ethyl-N′-3-(1-pyrrolidinyl)propyl-urea in 500 mL dichloromethane wasadded 62.6 g (0.62 mol) triethylamine and the solution was cooled to 0°C. To this solution were then added 59.17 g (0.31 mol) 4-toluenesulfonylchloride in 400 mL dichloromethane dropwise at such a rate as tomaintain the reaction at 0-5° C. After the addition was complete, thereaction mixture was warmed to room temperature and then heated toreflux for 4 hours. After cooling to room temperature, the reactionmixture was washed with saturated aqueous potassium carbonate (3×150mL). The aqueous phases were combined and extracted withdichloromethane. All organic phases were combined and concentrated underreduced pressure. The resultant orange slurry was suspended in 250 mLdiethyl ether and the solution decanted off from the solid. Theslurry/decantation process was repeated 3 more times. The ethersolutions were combined and concentrated under reduced pressure to give18.9 g (67%) of the desired product as a crude orange oil. A portion ofthe oil was distilled under vacuum to give a colorless oil distilling at78-82° C. (0.4 mm Hg).

Preparation of a Polymer Supported Form of1-(3-(1-Pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC)

A suspension of 8.75 g (48.3 mmol)1-(3-(1-pyrrolidin-yl)propyl)-3-ethylcarbodiimide and 24.17 g (24.17mmol) Merrifield's resin (2% cross-linked, 200-400 mesh,chloromethylated styrene/divinylbenzene copolymer, 1 meq. Cl/g) indimethylformamide was heated at 100° C. for 2 days. The reaction wascooled and filtered and the resulting resin washed sequentially with 1 LDMF, 1 L THF and 1 L diethyl ether. The remaining resin was then driedunder vacuum for 18 hours.

Example BB Preparation of Alanine iso-Butyl Ester Hydrochloride

A mixture of 35.64 g (0.4 mol) of (D,L)-alanine (Aldrich) (or L-alanine(Aldrich)); 44 mL (0.6 mol) of thionyl chloride (Aldrich) and 200 mL ofisobutanol was refluxed for 1.5 hours and the volatiles were removedcompletely on a rotavapor of 90° C. under reduced pressure to give(D,L)-alanine iso-butyl ester hydrochloride (or L-alanine iso-butylester hydrochloride), which was pure enough to be used for furthertransformations.

III. PREPARATION OF FINAL COMPOUNDS Example 1-1 Preparation of(S)-3-[(N′-(2-Thiophenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using 2-thiophenecarboxylic acidand(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 447 (M+H).

Example 1-2 Preparation of(S)-3-[(N′-(2-Furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using 2-furoic acid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 431 (M+H).

Example 1-3 Preparation of(S)-3-[(N′-(Cyclobutanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using cyclobutanecarboxylic acidand(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 419 (M+H).

Example 1-4 Preparation of(S)-3-[(N′-(1-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using1-phenyl-1-cyclopropanecarboxylic acid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 481 (M+H).

Example 1-5 Preparation of(S)-3-[(N′-(Cyclohexanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using cyclohexanecarboxylic acidand(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 447 (M+H).

Example 1-6 Preparation of(S)-3-[(N′-(2-Benzofurancarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using 2-benzofurancarboxylic acidand(S)-3-[(L-alaninyl))amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 481 (M+H).

Example 1-7 Preparation of(S)-3-[(N′-(5-Chlorobenzofuran-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using5-chlorobenzofuran-2-carboxylic acid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 515 (M+H).

Example 1-8 Preparation of(S)-3-[(N′-(5,5-Dimethyl-butyrolactone-yl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using terebic acid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 477 (M+H).

Example 1-9 Preparation of(S)-3-[(N′-(3-Furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 3-furoic acid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 523 (M+H).

Example 1-10 Preparation of(S)-3-[(N′-(4-(Methylsulfonyl)benzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following one or more of the general procedures outlined above, using4-(methylsulfonyl)benzoic acid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 519 (M+H).

Example 1-11 Preparation of(S)-3-[(N′-(trans-2-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above usingtrans-2-phenyl-1-cyclopropanecarboxylic acid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 481 (M+H).

Example 1-12 Preparation of(S)-3-[(N′-(5-Methylsulfonyl)thiophene-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following one or more of the general procedures outlined above, using(5-methylsulfonyl)thiophene-2-carboxylic acid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 525 (M+H).

Example 1-13 Preparation of(S)-3-[(N′-(1,8-Dimethyl-6-Hydroxy-bicyclo(2.2.2)octane-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using1,8-dimethyl-6-hydroxy-bicyclo(2.2.2)octane-2-carboxylic acid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 489 (M+H).

Example 1-14 Preparation of(S)-3-[(N′-(1,4-Benzodioxan-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 1,4-benzodioxan-2-carboxylicacid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 499 (M+H).

Example 1-15 Preparation of(S)-3-[(N′-(Tetrahydro-3-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using tetrahydro-3-furoic acid and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 435 (M+H).

Example 1-16 Preparation of(S)-3-[(N′-(3-Cyclohexenecarboxyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 3-cyclohexenecarboxylic acidand(S)-3-[(L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,the title compound was prepared. The molecular weight as determined bymass spectrometry (FD) was: 507 (M+H).

Example 1-17 Preparation of(S)-3-(N′-(Cyclopropanecarboxyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using cyclopropanecarboxylic acidand(S)-3-[(L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,the title compound was prepared. The molecular weight as determined bymass spectrometry (FD) was: 467 (M+H).

Example 1-18 Preparation of(S)-3-[(N′-(3,5-Difluorobenzoyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 3,5-difluorobenzoic acid and(S)-3-[(L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,the title compound was prepared. The molecular weight as determined bymass spectrometry (FD) was: 539 (M+H).

Example 1-19 Preparation of3-[(N′-(L-2-Pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure C-J above using L-pyroglutamic acid and3-[(L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,as described in Example C-AE, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 448 (M+H).

Example 1-21 Preparation of3-[(N′-(1-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure C-J above using1-phenyl-1-cyclopropanecarboxylic acid and3-[(L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,as described in Example C-AE, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 482 (M+H).

Example 1-22 Preparation of3-[(N′-(1-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure C-J above using1-phenyl-1-cyclopropanecarboxylic acid and3-[(L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,as described in Example C-AG, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 566 (M+H).

Example 1-23 Preparation of3-[(N′-(3,5-Difluorobenzoyl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure C-J above using 3,5-difluorobenzoic acid and3-[(L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,as described in Example C-AG, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 561 (M+H).

Example 1-24 Preparation of3-[(N′-(L-2-Pyrrolidinone-5-yl)-L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure C-J above using L-pyroglutamic acid and3-[(L-alaninyl)]amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,as described in Example C-AG, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 533 (M+H).

Example 1-26 Preparation of3-[(N′-(1-Phenyl-1-cyclopropanecarboxyl)-L-alaninyl)]amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure C-J above using1-phenyl-1-cyclopropanecarboxylic acid and3-[(L-alaninyl)]amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,as described in Example C-AF, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 567 (M+H).

Example 1-27 Preparation of3-[(N′-(4-Methylbenzoyl)-D-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following one or more of the general procedures outlined above, using4-methylbenzoic acid and3-[(D-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,the title compound was prepared. The molecular weight as determined bymass spectrometry (FD) was: 517 (M+H).

Example 1-28 Preparation of3-[(N′-(4-Methylbenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following one or more of the general procedures outlined above, using4-methylbenzoylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 455 (M+H).

Example 1-30 Preparation of3-[(N′-(2-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using 2-naphthoic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was:491 (M+H).

Example 1-31 Preparation of3-[(N′-(1-Naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using 1-naphthoic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: (M+H).

Example 1-32 Preparation of3-[(N′-(5-Chloro-2-thiophenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using5-chloro-2-thiophenecarboxylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 481 (M+H).

Example 1-33 Preparation of3-[(N′-(4-Cyanobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using 4-cyanobenzoic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 466 (M+H).

Example 1-34 Preparation of3-[(N′-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using tetrahydro-2-furoic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 466 (M+H).

Example 1-35 Preparation of3-[(N′-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using 3,5-difluorobenzoic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 477 (M+H).

Example 1-36 Preparation of3-[(N′-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using 3-cyclohexenecarboxylic acidand3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 445 (M+H).

Example 1-37 Preparation of3-[(N′-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using1,2,3,4-tetrahydro-2-naphthoic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 495 (M+H).

Example 1-38 Preparation of3-[(N′-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using cyclopentanecarboxylic acidand3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 433 (M+H).

Example 1-39 Preparation of (S)-3-[(N′-(4-(Trifluoromethyl)cyclohexaneCarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using trifluoromethyl)cyclohexanecarboxylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 515 (M+H).

Example 1-40 Preparation of(S)-3-[(N′-(Bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using(bicyclo[2.2.1]heptane-2-carboxylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 459 (M+H).

Example 1-41 Preparation of(S)-3-[(N′-(Bicyclo(2.2.1)hept-5-ene-2-carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above usingbicyclo(2.2.1)hept-5-ene-2-carboxylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 457 (M+H).

Example 1-42 Preparation of (S)-3-[(N′-(2,2-DichlorocyclopropaneCarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 2,2-dichlorocyclopropanecarboxylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 473 (M+H).

Example 1-43 Preparation of(S)-3-[(N′-(Cycloheptanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using cycloheptanecarboxylic acidand3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 461 (M+H).

Example 1-44 Preparation of(S)-3-[(N′-(1-(2,4-Dichlorophenyl)cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using2,4-dichlorophenyl)cyclopropanecarboxylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: (M+H).

Example 1-45 Preparation of(S)-3-[(N′-(2-Methylcyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 2-methylcyclopropanecarboxylicacid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 419 (M+H).

Example 1-46 Preparation of(S)-3-[(N′-(1-(4-Chlorophenyl)-1-cyclobutanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using4-chlorophenyl)-1-cyclobutanecarboxylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 529 (M+H).

Example 1-47 Preparation of(S)-3-[(N′-(2-Biphenylcarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 2-biphenylcarboxylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 517 (M+H).

Example 1-48 Preparation of(S)-3-[(N′-(1,2-Dihydro-1-oxo-2-phenyl-4-isoquinolinecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using1,2-dihydro-1-oxo-2-phenyl-4-isoquinolinecarboxylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 584 (M+H).

Example 1-49 Preparation of (S)-3-[(N′-(Bicyclo(3.3.1)non-6-ene-3-Carboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using bicyclo(3.3.1)non-7-ene-3-carboxylic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 485 (M+H).

Example 1-50 Preparation of(S)-3-[(N′-(Cyclopropanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using cyclopropanecarboxylic acidand3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 405 (M+H).

Example 1-51 Preparation of(S)-3-[(N′-(Tetrahydro-2-furoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using tetrahydro-2-furoic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 435 (M+H).

Example 1-52 Preparation of(S)-3-[(N′-(3,5-Difluorobenzoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 3,5-difluorobenzoic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 477 (M+H).

Example 1-53 Preparation of(S)-3-[(N′-(3-Cyclohexenecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 3-cyclohexenecarboxylic acidand3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 445 (M+H).

Example 1-54 Preparation of(S)-3-[(N′-(1,2,3,4-Tetrahydro-2-naphthoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 1,2,3,4-tetrahydro-2-naphthoicacid and(S)-3-(-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 495 (M+H).

Example 1-55 Preparation of(S)-3-[(N′-(Cyclopentanecarboxyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using cyclopentanecarboxylic acidand3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-11H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 433 (M+H).

Example 1-56 Preparation of5-{N′-(Tetrahydro-3-furoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P above using tetrahydro-3-furoic acid and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 408 (M+H).

Example 1-57 Preparation of 5-{N′-(CyclopropaneCarboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P above using cyclopropane carboxylic acidand5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 378 (M+H).

Example 1-59 Preparation of5-{N′-(Bicyclo[2.2.1]heptane-2-carboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P above usingbicyclo[2.2.1]heptane-2-carboxylic acid and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 432 (M+H).

Example 1-60 Preparation of5-{N′-(Tetrahydro-2-furoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P above using tetrahydro-2-furoic acid and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 408 (M+H).

Example 1-61 Preparation of5-{N′-(Cyclopentanecarboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P above using cyclopentanecarboxylic acidand5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 406 (M+H).

Example 1-62 Preparation of5-{N′-(2-Thiophenecarboxyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P above using 2-thiophenecarboxylic acidand5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 420 (M+H).

Example 2-1 Preparation of(S)-3-[(N′-(2,3-Diphenylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using 2,3-diphenylpropionic acidand3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 545 (M+H).

Example 2-2 Preparation of(S)-3-[(N′-(2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using 2-phenoxypropionic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 485 (M+H).

Example 2-4 Preparation of(S)-3-[(N′-(2-Isopropyl-2-phenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using 2-isopropyl-2-phenylaceticacid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 497 (M+H).

Example 2-5 Preparation of(S)-3-[(N′-(2-Ethylhexanoyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using 2-ethylhexanoic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 463 (M+H).

Example 2-6 Preparation of(S)-3-[(N′-(2-Methylbutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using 2-methylbutyric acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 421 (M+H).

Example 2-7 Preparation of(S)-3-[(N′-(2-Methyl-4,4,4-trifluorobutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using2-methyl-4,4,4-trifluorobutyric acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 475 (M+H).

Example 2-8 Preparation of(S)-3-[(N′-(Diphenylacetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using diphenylacetic acid and3-[(L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 593 (M+H).

Example 2-9 Preparation of(S)-3-[(N′-(4-Chloro-α-methylphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 4-chloro-α-methylphenylaceticacid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 503 (M+H).

Example 2-10 Preparation of(S)-3-[(N′-(4-Chloro-α,α-dimethylphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using4-chloro-α,α-dimethylphenylacetic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 517 (M+H).

Example 2-11 Preparation of(S)-3-[(N′-((S)-(+)-2-Hydroxy-2-phenylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using(S)-(+)-2-hydroxy-2-phenylpropionic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 485 (M+H).

Example 2-12 Preparation of(S)-3-[(N′-(α-Hydroxy-diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Following one or more of the general procedures outlined above, usingα-hydroxy-diphenylacetic acid and(S)-3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,as described in Example C-AE, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 548 (M+H).

Example 2-17 Preparation of(S)-3-[(N′-(α-Hydroxy-diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-2-(diethylamino)ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Following one or more of the general procedures outlined above, usingα-hydroxy-diphenylacetic acid and(S)-3-(L-alaninyl)amino-2,3-dihydro-1-2-(diethylamino)ethyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,the title compound was prepared. The molecular weight as determined bymass spectrometry (FD) was: 633 (M+H).

Example 2-18 Preparation of3-[N′-(3,5-Difluorophenyl-α-hydroxy-α-methylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one

A. Preparation of 3,5-Difluorophenyl-α-hydroxy-α-methylacetic Acid

The compound was prepared according to the general procedure of Stilleret al., J. Med. Chem., 15:1029 (1972). A solution ofalpha-keto-3,5-difluorophenylacetic acid (prepared according toMiddleton et al., J. Org Chem., 45:2883 (1980)) in diethyl ether wascooled to 0° C. Methylmagnesium chloride (4.7 eq., 3.0 M solution inTHF) was added dropwise via syringe pump at a rate of 10 ml/min so thatthe internal temperature did not exceed 5.5° C. The cooling bath wasremoved and stirring continued at ambient for 1.5 hours. Afterapproximately 30 minutes, the clumps of solid dissolved. The mixture waspoured onto ice and acidified with 1N HCl. The aqueous layer wasextracted thrice with ethyl acetate. The combined organics were washedwith 5% NaHSO₃, water and brine. The organic layer was dried over sodiumsulfate, filtered, and concentrated to a yellowish solid. The solid wasrecrystallized from dichloromethane, giving a white crystalline solidhaving a melting point of 102.5-103.2 C. C9H8F2O3 (MW 202.17); massspectroscopy found (M−H) 201.2. Anal calcd for C9H8F2O3: C, 53.47, H,3.99. Found: C, 53.76; H, 3.82.

B. Preparation of the Title Compound

Following General Procedure D above using3,5-difluorophenyl-α-hydroxy-α-methylacetic acid and3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one(Example 8-b), the title compound was prepared. ¹H NMR (CDCl₃, 300 MHz)δ=1.43 (3H, d, J=7.1 Hz), 1.79 (3H, s), 3.47 (3H, s), 4.15 (1H, s), 4.58(1H, p, J=7.3 Hz), 5.45 (1H, d, J=8.0 Hz), 6.70 (1H, m), 7.14-7.27 (3H,m), 7.32-7.47 (6H, m), 7.55-7.63 (3H, m), 7.78 (1H, d, J=7.8 Hz). HRMScalc for C28H27N4O4F2 521.2000 (MH⁺), Found: 521.2.

Example 2-19 Preparation of3-[N′-(3,5-Difluorophenyl-α-hydroxy-α-methylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one

Following General Procedure D above using3,5-difluorophenyl-α-hydroxy-α-methylacetic acid (described above inExample 2-18) and3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one(Example 8-b), the title compound was prepared.

¹H NMR (CDCl₃, 300 MHz) δ=1.48 (3H, d, J=7.0 Hz), 1.78 (3H, s), 3.45(3H, s), 3.86 (1H, s), 4.62 (1H, p, J=7.1 Hz), 5.42 (1H, d, J=7.6 Hz),6.69 (1H, m), 7.13-7.59 (12H, m), 7.67 (1H, d, J=7.6 Hz). HRMS calc forC28H27N4O4F2 521.2000 (MH⁺), Found: 521.2.

Example 2-20 Preparation of3-[(N′-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using diphenylacetic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 531 (M+H).

Example 2-21 Preparation of3-[(N′-(Acetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-A above using acetic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 379 (M+H).

Example 2-22 Preparation of(S)-3-[(N′-(2-Methylvaleryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 2-methylvaleric acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 435 (M+H).

Example 2-23 Preparation of(S)-3-[(N′-(α-(Hydroxymethyl)phenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using α-(hydroxymethyl)phenylaceticacid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 485 (M+H).

Example 2-24 Preparation of(S)-3-[(N′-(2-Ethylbutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 2-ethylbutyric acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 435 (M+H).

Example 2-25 Preparation of(S)-3-[(N′-(Pivalyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using pivalic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 421 (M+H).

Example 2-26 Preparation of(S)-3-[(N′-(Diphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using diphenylacetic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 531 (M+H).

Example 2-27 Preparation of(S)-3-[(N′-(Acetyl)-L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using acetic acid and3-[(L-phenylglycinyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 441 (M+H).

Example 2-28 Preparation of3-[N′-(2-Thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 2-thioacetyl-3-methyl butanoicacid (Coric et al., J. Med. Chem. 39, 1210 (1996)) and3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B, the title compound was prepared.

¹H NMR (CDCl₃, 300 MHz) δ 1.01 (6H, d, J=6.8 Hz), 1.04 (3H, d, J=7.2Hz), 1.07 (3H, d, J=6.8 Hz), 1.45 (3H, d, J=6.8 Hz), 1.49 (3H, d, J=7.2Hz), 2.35 (2H, m), 2.38 (3H, s), 2.40 (3H, s), 3.45 (3H, s), 3.46 (3H,s), 3.84 (1H, d, J=7.9 Hz), 3.85 (1H, d, J=7.9 Hz), 4.63 (2H, m), 5.47(1H, d, J=7.9 Hz), 5.48 (1H, d, J=7.9 Hz), 6.73 (1H, d, J=8.4 Hz), 6.80(1H, d, J=7.5 Hz), 7.20-7.62 (20H, m). MS calcd for C26H31N4O4S 495.21(MH⁺), found 495.2.

Example 2-29 Preparation of3-[N′-(2-Mercapto-3-methyl-butanoyl)-L-alaninyl]-amino-2,3-dihydro-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

A solution of3-[N′-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-oneas prepared in Example 2-28 in degassed methanol was treated withdegassed 1N NaOH (3 equiv.). After stirring at ambient temperature for 3hours, the reaction was acidified to pH 1 by adding 1N HCl. The solutionwas concentrated in vacuo; the residue was partitioned between ethylacetate and brine. The organic phase was dried over sodium sulfate,filtered, and concentrated to afford the title compound.

¹H NMR (CDCl₃, 300 MHz) δ 0.99 (3H, d, J=6.0 Hz), 1.01 (3H, d, J=6.8Hz), 1.05 (3H, d, J=6.4 Hz), 1.06 (3H, d, J=6.8 Hz), 1.51 (6H, d, J=6.8Hz), 1.90 (1H, d, J=8.8 Hz), 1.91 (1H, d, J=8.8 Hz), 2.31 (2H, o, J=6.8Hz), 3.17 (1H, dd, J=9.2 Hz), 3.22 (1H, dd, H=6.4, 8.8 Hz), 3.48 (6H,s), 4.67 (2H, p, J=6.8 Hz), 5.48 (1H, d, J=7.6 Hz), 5.49 (1H, d, J=7.6Hz), 7.04 (1H, d, J=7.2 Hz), 7.09 (1H, d, J=7.2 Hz), 7.23-7.27 (2H, m),7.34-7.40 (8H, m), 7.45-7.49 (2H, m), 7.58-7.64 (8H, m). MS calcd forC24H29N4O3S 453.20 (MH⁺), found 453.1.

Example 2-30 Preparation of5-{N′-(2-Phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P above using 2-phenylpropionic acid and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 442 (M+H).

Example 2-31 Preparation of5-{N′-(2-Methylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P above using 2-methylhexanoic acid and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 422 (M+H).

Example 2-32 Preparation of5-{N′-(Diphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P above using diphenylacetic acid and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 504 (M+H).

Example 2-33 Preparation of5-{N′-((S)-(+)-2-Hydroxy-2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following one or more of the general procedures outlined above, using(S)-(+)-2-hydroxy-2-phenylpropionic acid and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 458 (M+H).

Example 2-34 Preparation of5-{N′-((R)-(−)-2-Hydroxy-2-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following one or more of the general procedures outlined above, using(R)-(−)-2-hydroxy-2-phenylpropionic acid and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 458 (M+H).

Example 2-35 Preparation of5-{N′-(2-Hydroxy-2-methylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General procedure D above using 2-methyllactic acid (Aldrich)and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The productwas purified by flash chromatography CHCl₃/MeOH (98:2) to yield thetitle compound.

C22H₂₅N3O4 (MW=395.457); mass spectroscopy (MH⁺) 396. Anal. Calcd forC22H₂₅N3O4; C, 66.06; H, 6.25; N, 10.50. Found: C, 65.91; H, 6.30; N,10.52.

Example 2-36 Preparation of5-{N′-(2-Hydroxy-2-methylbutanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,as described in Example 7-B, and 2-hydroxy-2-methylbutyric acid(Aldrich) the title compound was prepared. The product was purified byflash chromatography (CHCl₃/MeOH (98:2) yielding the title compound.

C23H27N3O4 (MW=409-483); mass spectroscopy (MH⁺) 410. Anal. Calcd forC23H27N3O4; C, 67.46; H, 6.65; N, 10.26. Found: C, 67.63; H, 6.64; N,10.31.

Example 2-37 Preparation of5-(S)-[N′-(2-Thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6one

Following General Procedure D, using 2-thioacetyl-3-methylbutanoic acidand5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared.

¹H NMR (CDCl₃, 300 MHz) δ 0.86-0.96 (12H, m), 1.25 (3H, d, J=7.2 Hz),2.05 (2H, m), 2.33 (3H, s), 2.35 (3H, s), 3.25 (6H, s), 4.02 (2H, m),4.56 (2H, m), 5.09 (1H, d, J=7.9 Hz), 5.12 (1H, d, H=7.9 Hz), 7.39-7.70(16H, m), 8.48 (1H, d, J=7.2 Hz), 8.53 (1H, d, J=7.5 Hz), 8.56 (2H, d,J=8.3 Hz). MS calcd for C₂₅H₃₀N₃O₄S 468.20 (MH⁺), found 468.2.

Example 2-38 Preparation of5-{N′-(Acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P using acetic acid and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 352 (M+H).

Example 2-39 Preparation of5-(S)-[N′-(2-Mercapto-3-methylbutanoyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

A solution of5-(S)-[N′-(2-thioacetyl-3-methyl-butanoyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 2-37) in degassed methanol was treated with degassed 1N NaOH (3equiv.). After stirring at ambient temperature for 3 hours, the reactionwas acidified to pH 1 by adding 1N HCl. The solution was concentrated invacuo; the residue was partitioned between ethyl acetate and brine. Theorganic phase was dried over sodium sulfate, filtered, and concentratedto afford the title compound.

¹H NMR (CDCl₃, 400 MHz) δ 0.98 (6H, d, J=6.8 Hz), 1.03 (6H, d, J=6.8Hz), 1.45 (3H, d, J=7.6 Hz), 1.46 (3H, d, J=6.8 Hz), 1.88 (1H, d, J=8.8Hz), 1.89 (1H, d, J=8.8 Hz), 2.29 (2H, m), 3.15 (1H, dd, J=6.4, 8.8 Hz),3.18 (1H, dd, J=6.4, 8.8 Hz), 3.36 (6H, s), 4.71 (2H, m), 5.27 (2H, d,J=6.8 Hz), 6.95 (1H, d, J=7.2 Hz), 7.02 (1H, d, J=7.2 Hz), 7.30-7.67(18H, m). MS calcd for C23H28N3O3S 426.18 (MH⁺), found 426.1.

Example 3-1 Preparation of(S)-3-[(N′-(trans-Cinnamyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using trans-cinnamic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 467 (M+H).

Example 3-2 Preparation of3-[(N′-(trans-Cinnamyl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure C-J above using trans-cinnamic acid and3-[(N′-(trans-cinnamyl)-L-alaninyl)]amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,as described in Example C-AE, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 468 (M+H).

Example 3-5 Preparation of5-{N′-(trans-Cinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure C-P above using trans-cinnamic acid and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 440 (M+H).

Example 4-1 Preparation of(S)-3-[(N′-(2-Phenoxybutyryl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using 2-phenoxybutyric acid and3-[(L-alaninyl)]amino-2,3dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 499 (M+H).

Example 4-2 Preparation of(S)-3-[(N′-((R,S)-(−)-α-Methoxyphenylacetyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using(R,S)-(−)-α-methoxyphenylacetic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 485 (M+H).

Example 4-3 Preparation of(S)-3-[(N′-(2-(4-Chlorophenoxy)-2-methylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using2-(4-chlorophenoxy)-2-methylpropionic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 533 (M+H).

Example 4-4 Preparation of(S)-3-[(N′-((R,S)-2-Phenoxypropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure C-B above using (R,S)-2-phenoxypropionicacid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 485 (M+H).

Example 4-5 Preparation of3-[N′-(3,5-Difluorophenyl-α-methoxyacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-Benzodiazepin-2-one

A. Preparation of 3,5-Difluorophenyl-α-methoxyacetic Acid

The title compound was prepared according to the general procedure inReeve, et al, _(J.A.C.S)., 83 :2755 (1961). A solution of3,5-difluorobenzaldehyde (Aldrich) and bromoform (1.2 eq.) In methanolwas cooled to −5° C. and treated dropwise with methanolic KOH. Thereaction temperature was held below 6 C during the addition. The mixturewas slowly warmed to room temperature and stirred overnight. Thesuspension was diluted with water and 50% saturated aqueous brine. Themixture was extracted with ether, and the aqueous layer was acidified toa pH around 3.5 and extracted with ether. The latter organic phase wasdried over sodium sulfate, filtered and concentrated. The crude acid waspurified via flash chromatography eluting with 1:4:95 aceticacid/methanol/methylene chloride to give a white solid. ¹H NMR (300 MHz,CDCl₃) δ 11.36 (1H, bs), 7.05 (1H, m), 6.81 (2H, tt, J=2.4, 8.8 Hz),4.77 (1H, s), 3.47 (3H, s)/C9H8F2O3 (MW=202.17); mass spectroscopy—202.

B. Following General Procedure D above using3,5-difluorophenyl-α-methoxyacetic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared.Anal. Calcd for C₂₈H₂₈F₂N₄O₄; C, 64.61; H, 5.03; N, 10.76. Found: C,64.36; H, 5.23; N, 10.53. MS calcd for C₂₈H₂₈F₂N₄O₄ 520.5, found 520.0.

Example 4-6 Preparation of3-[N′-(3,5-Difluorophenyl-α-methoxyacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using3,5-difluorophenyl-α-methoxyacetic acid (as described in Example 4-5)and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared.Anal. Calcd for C₂₈H₂₈F₂N₄O₄; C, 64.61; H, 5.03; N, 10.76. Found: C,64.85; H, 5.18; N, 10.76. MS calcd for C₂₈H₂₈F₂N₄O₄ 520.5, found 519.9.

Example 4-7 Preparation of3-[(N′-(2-(4-Hydroxyphenoxy)propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 2-(4-hydroxyphenoxy)propionicacid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 501 (M+H).

Example 4-8 Preparation of(S)-3-[(N′-(2-(4-Trifluorophenyoxy)propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following one or more of the general procedures outlined above, using2-(4-trifluorophenyoxy)propionic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 469 (M+H).

Example 4-9 Preparation of(S)-3-[(N′-(2-(4-Biphenylyloxy)propionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using 2-(4-biphenylyloxy)propionicacid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 561 (M+H).

Example 4-15 Preparation of3-[(N′-(α-Methoxyphenylacetyl)-L-alaninyl)]amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Following General Procedure C-J above using α-methoxyphenylacetic acidand3-(L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,as described in Example C-AF, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 571 (M+H).

Example 4-16 Preparation of(S)-3-[(N′-(2-(4-Cyanophenoxy)-2-methylpropionyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using2-(4-cyanophenoxy)-2-methylpropionic acid and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 524 (M+H).

General Procedure 5-A1 for Urea Preparation

In a round bottom flask was added an amine (1.0 eq.) in THF or CH₂Cl₂followed by an isocyanate (1.0 eq.). The reaction mixture was allowed tostir 2-20 hours at room temperature under an atmosphere of nitrogen. Themixture was diluted with EtOAc or CH₂Cl₂ and washed with saturatedNaHCO₃ (1×5mL), H₂O (1×5 mL), and brine and dried over MgSO₄. The dryingagent was removed by filtration and the filtrate was concentrated invacuo. The residue was either purified by trituration or silica gelflash chromatography.

General Procedure (5-B1)—Urea Preparation

5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (1.0 eq) methylene chloride (CH₂Cl₂), triethylamine (1.5eq), and a suitable isocyanate (4 eq) are combined in a brown glass vialand placed on an orbital shaker for 5-48 hours. At this timeaminomethylated polystyrene resin (Aldrich) (6 eq) is added and themixture is shaken for an additional 5-24 hours. The reaction mixture isthen filtered, the flask washed with an additional 15 mL CH2Cl2, and thefiltrate removed in vacuo. The remaining solid is then purified bypassing through a small silica gel plug with ethyl acetate (EtOAc). Thesolvent is removed in vacuo to yield the product as a white solid. Theproduct is then analyzed by reverse phase HPLC (Waters C18 mBondapak3.9×300mm column, eluent: 30% CH3CN in 0.1% aqueous triflouroaceticacid, UV detection: 233 nm). Ionspray-MS is also used to analyze theproducts.

General Procedure (5-C1)—Urea Preparation

A solution of5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) (1.0 eq) in dichloromethane is stirred at 0°C. with aqueous saturated sodium bicarbonate solution. After 15 minutes,the stirring is stopped and the layers allowed to separate. A phosgenesolution (20% in toluene, Aldrich, 2.0 eq) is added to the organiclayer, and stirring is resumed. After 15 additional minutes of stirringat 0° C., the layers are separated, and the organic layer is washed withaqueous saturated sodium bicarbonate solution, dried over anhydroussodium sulfate and the solvents removed in vacuo to yield a colorlessoil. This oil is diluted with dichloromethane, and transferred to abrown glass vial. A suitable amine (4 eq) is added, and the vial isplaced on an orbital shaker, and shaken for 3-28 hours. At this time,aminomethylated polystyrene resin (6 eq, Aldrich) is added, and shakingcontinued for 4-28 hours. The reaction mixture is filtered through asintered glass funnel, the solvents removed in vacuo to yield theproduct as a white solid. The product is characterized by reverse phaseHPLC (Waters 3.9×300 mBondapak column, eluent: 30% acetonitrile in 0.1%aqueous triflouroacetic acid buffer, monitored by UV detection @ 233 nm)and IEX-MS.

General Procedure (5-D1)—Urea Preparation

A solution of5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) (1.0 eq) in dichloromethane is stirred at 0°C. with aqueous saturated sodium bicarbonate solution. After 15 minutes,the stirring is stopped and the layers allowed to separate. A phosgenesolution (20% in toluene, Aldrich, 2.0 eq) is added to the organiclayer, and stirring is resumed. After 15 additional minutes of stirringat 0° C., the layers are separated, and the organic layer is washed withaqueous saturated sodium bicarbonate solution, dried over anhydroussodium sulfate and the solvents removed in vacuo to yield a colorlessoil. This oil is diluted with dichloromethane, and a suitable amine isadded (1.5-4 eq). The reaction mixture is stirred for 17 hours, at whichtime the reaction mixture is washed with 0.1N HCl. The organic layer isdried over anhydrous sodium sulfate, and the solvents removed in vacuo.Purification by chromatography provides the product as a white solid.

Example 5-1 Preparation of(S)-3-[(N′-((trans-2-Phenylcyclopropyl)ureylenyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using trans-2-phenylcyclopropylisocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 495 (M+H).

Example 5-2 Preparation of(S)-3-[(N′-((3,4-Dichlorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 3,4-dichlorophenyl isocyanateand(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 523 (M+H).

Example 5-3 Preparation of(S)-3-[(N′-((2-Propenyl)aminocarbonyl)-]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2-propenyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: (M+H).

Example 5-4 Preparation of(S)-3-[(N′-((R)-(−)-1-(1-Naphthyl)ethyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using (R)-(−)-1-(1-naphthyl)ethylisocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 533 (M+H).

Example 5-5 Preparation of(S)-3-[(N′-((2,6-Diisopropylphenyl)aminocarbonyl)-L-alaninyl-]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2,6-diisopropylphenylisocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 539 (M+H).

Example 5-6 Preparation of(S)-3-[(N′-((3-[(Trifluoromethyl)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 3-[(trifluoromethyl)phenylisocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 523 (M+H).

Example 5-7 Preparation of(S)-3-[(N′-((Phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using phenyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 455 (M+H).

Example 5-8 Preparation of(S)-3-[(N′-((4-Ethoxycarbonylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 4-ethoxycarbonylphenylisocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 527 (M+H).

Example 5-9 Preparation of(S)-3-[(N′-((2-Bromophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2-bromophenyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 534 (M+H).

Example 5-10 Preparation of(S)-3-[(N′-((o-Tolyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using o-tolyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 469 (M+H).

Example 5-11 Preparation of(S)-3-[(N′-((2-Ethyl-6-methylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2-ethyl-6-methylphenylisocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 497 (M+H).

Example 5-12 Preparation of(S)-3-[(N′-((2-Fluorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2-fluorophenyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 473 (M+H).

Example 5-13 Preparation of(S)-3-[(N′-((2,4-Difluorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2,4-difluorophenyl isocyanateand(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 491 (M+H).

Example 5-14 Preparation of(S)-3-[(N′-((2-Ethoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2-ethoxyphenyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 499 (M+H).

Example 5-15 Preparation of(S)-3-[(N′-((3-Acetylphenyl)aminocarbonyl)-L-alaninyl-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 3-acetylphenyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 497 (M+H).

Example 5-16 Preparation of(S)-3-[(N′-((3-[(Cyano)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 3-[(cyano)phenyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 501 (M+H).

Example 5-18 Preparation of(S)-3-[(N′-((Phenethyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using phenethyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 483 (M+H).

Example 5-19 Preparation of(S)-3-[(N′-((4-n-Butylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 4-n-butylphenyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 511 (M+H).

Example 5-20 Preparation of(S)-3-[(N′-((Octyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using octyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 491 (M+H).

Example 5-21 Preparation of(S)-3-[(N′-((4-Biphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 4-biphenyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 531 (M+H).

Example 5-22 Preparation of(S)-3-[(N′-((4-Isopropylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 4-isopropylphenyl isocyanateand(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 497 (M+H).

Example 5-23 Preparation of(S)-3-[(N′-((Hexyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using hexyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 463 (M+H).

Example 5-24 Preparation of(S)-3-[(N′-((2-Isopropylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2-isopropylphenyl isocyanateand(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 513 (M+H).

Example 5-25 Preparation of(S)-3-[(N′-((2,6-Difluorophenyl)aminocarbonyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2,6-difluorophenyl isocyanateand(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 491 (M+H).

Example 5-26 Preparation of(S)-3-[(N′-((Octadecyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using octadecyl isocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 631 (M+H).

Example 5-27(S)-3-[(N′-((4-(Trifuoromethoxy)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using trifluoromethoxy)phenylisocyanate and(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 539 (M+H).

Example 5-28 Preparation of(S)-3-[(N′-((2,4-Dichlorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2,4-dichlorophenyl isocyanateand(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 524 (M+H).

Example 5-29 Preparation of(S)-3-[(N′-((3-Ethoxycarbonylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using ethoxycarbonylphenyl isocyanateand(S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 527 (M+H).

Example 5-30 Preparation of(S)-3-[(N′-((4-Chlorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 4-chlorophenyl isocyanate and(S)-3-[(N′-((4-Chlorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 489 (M+H).

Example 5-31 Preparation of(S)-3-[(N′-((4-Butoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 4-butoxyphenyl isocyanate and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 547 (M+H).

Example 5-32 Preparation of(S)-3-[(N′-((4-Phenoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 4-phenoxyphenyl isocyanate and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 527 (M+H).

Example 5-33 Preparation of(S)-3-[(N′-((1-Naphthyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using naphthyl isocyanate and(S)-3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 505 (M+H).

Example 5-34 Preparation of(S)-3-[(N′-((2-Biphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using (2-phenyl)phenyl isocyanate and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 531 (M+H).

Example 5-35 Preparation of(S)-3-[(N′-((2-(Methylthio)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2-(methylthio)phenyl isocyanateand3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 501 (M+H).

Example 5-36 Preparation of(S)-3-[(N′-((2-Ethylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2-ethylphenyl isocyanate and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 483 (M+H).

Example 5-37 Preparation of(S)-3-[(N′-((3-Methoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 3-methoxyphenyl isocyanate and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 485 (M+H).

Example 5-38 Preparation of(S)-3-[(N′-((3,4,5-Trimethoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 3,4,5-trimethoxyphenylisocyanate and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 545 (M+H).

Example 5-39 Preparation of(S)-3-[(N′-((2,4,6-Trimethylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2,4,6-trimethylphenylisocyanate and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: 497 (M+H).

Example 5-40 Preparation of,(S)-3-[(N′-((2-Methyl-6-t-butylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2-methyl-6-t-butylphenylisocyanate and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: (M+H).

Example 5-41 Preparation of(S)-3-[(N′-((2-(2-Thiophene-yl)ethyl)aminocarbonyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure (5-A1) using 2-thiophene-yl isocyanate and3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: (M+H).

Example 5-43 Preparation of5-(S)-(N′-((2-(Thiophen-2-yl)ethylaminocarbonyl)-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-A1) using 2-(thien-2-yl)ethyl isocyanateand5-(S)-(N′-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,as described in Example 7-B, the title compound was prepared as a whitesolid. The reaction was monitored by tlc (R_(f)=0.35 in 10% MeOH/CH₂Cl₂)and the product was purified by silica gel chromatography using gradientelution of MeOH/CH₂Cl₂ (1:99-2:98).

NMR data was as follows:

¹H-nmr (CDCl₃): delta=7.86 (d, J=7.0 Hz, 1H), 7.51-7.24 (m, 10H), 7.06(d, J=6.0 Hz, 1H), 6.87-6.84 (m, 1H), 6.72-6.71 (m, 1H), 5.20 (d, J=6.5Hz, 1H), 4.554.53 (m, 1H), 3.27 (s, 3H), 3.20-3.05 (m, 2H), 2.75-2.70(m, 2H), 1.25 (d, J=7.0 Hz, 3H). C₂₅H₂₆N₄O₃S (MW=462.57); massspectroscopy (MH⁺) 463.6. Anal Calcd for C₂₅H₂₆N₄O₃S, C, 64.91; H, 5.67;N, 12.1 1; Found: C, 65.12; H, 5.71; N, 12.10.

Example 5-44 Preparation of5-(S)-(N′-((Phenethylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-A1) using phenethyl isocyanate and5-(S)-(N′-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,the title compound was prepared as a white solid. The reaction wasmonitored by tlc (R_(f)=0.53 in 10% MeOH/CH₂Cl₂) and the product waspurified by silica gel chromatography using gradient elution ofMeOH/CH₂Cl₂ (1:99-3:97).

NMR data was as follows:

¹H-nmr (CDCl₃): δ=7.78 (d, J=6.6 Hz, 1H), 7.54-7.12 (m, 15H), 5.23 (d,J=6.7 Hz, 1H), 4.584.53 (m, 1H), 3.32-3.27 (m, 5H), 2.64 (t, J=7.4 Hz,2H), 1.33 (d, J=7.0 Hz, 3H). Optical Rotation: [α]₂₀=−80.3 @ 589 nm(c=1, MeOH); C₂₇H₂₈N₄O₃ (MW=456.5); mass spectroscopy (MH⁺) 457.5; AnalCalcd for C₂₇H₂₈N₄O₃; C, 71.03; H, 6.18; N, 12.27; Found: C, 70.90; H,6.38; N, 12.00.

Example 5-45 Preparation of5-(S)-(N′-((Butylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-A1) using butyl isocyanate and5-(S)-(N′-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,as described in Example 7-B, the title compound was prepared as a whitesolid. The reaction was monitored by tlc (R_(f)=0.49 in 10% MeOH/CH₂Cl₂)and the product was purified by silica gel chromatography using gradientelution of MeOH/CH₂Cl₂ (1:99-3:97).

NMR data was as follows:

¹H-nmr (CDCl₃): delta=7.74-7.33 (m, 11H), 5.24 (d, J=6.7 Hz, 1H),4.57-4.53 (m, 1H), 3.35 (s, 3H), 3.08-2.85 (m, 2H), 1.39-1.25 (m, 7H),0.88 (t, J=7.0 Hz, 3H). Optical Rotation: [α]₂₀=−97.1 @ 589 nm (c=1,MeOH); C₂₃H₂₈N₄O₃ (MW=408.5); mass spectroscopy (MH⁺) 409.4; Anal Calcdfor C₂₃H₂₈N₄O₃; C, 67.63; H, 6.91; N, 13.72; Found: C, 67.46; H, 6.93;N, 13.64.

Example 5-46 Preparation of5-(S)-(N′-((Benzylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-A1) using benzyl isocyanate and5-(S)-(N′-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,as described in Example 7-B, the title compound was prepared as a whitesolid. The reaction was monitored by tlc (R_(f)=0.63 in 10% MeOH/CH₂Cl₂)and the product was purified by trituration from EtOAc and Hex.

NMR data was as follows:

¹H-nmr (CDCl₃): δ=7.86 (d, J=6.7 Hz, 1H), 7.46-7.09 (m, 15H), 5.21 (d,J=6.7 Hz, 1H), 4.594.40 (m, 1H), 4.384.00 (m, 2H), 3.27 (s, 3H), 1.29(d, J=7.1 Hz, 3H). C₂₆H₂₆N₄O₃ (MW=442.52); mass spectroscopy (MH⁺)443.3. Anal Calcd for C₂₆H₂₆N₄O₃; C, 70.57; H, 5.92; N, 12.66; Found: C,70.36; H, 6.05; N, 12.47.

Example 5-47 Preparation of5-(S)-(N′-((Ethylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-A1) using ethyl isocyanate and5-(S)-(N′-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,as described in Example 7-B, the title compound was prepared as a whitesolid. The reaction was monitored by tlc (R_(f)=0.35 in 10% MeOH/CH₂Cl₂)and the product was purified by silica gel chromatography using gradientelution of MeOH/CH₂Cl₂ (1:99-4:96).

NMR data was as follows:

¹H-nmr (CDCl₃): δ=7.84 (d, J=6.8 Hz, 1H), 7.56-7.30 (m, 10H), 5.23 (d,J=6.7 Hz, 1H), 4.60-4.53 (m, 1H), 3.33 (s, 3H), 3.00-2.87 (m, 2H), 1.30(d, 7.0Hz, 3H), 0.85 (t, J=7.1 Hz, 3H). C₂₁H₂₄N₄O₃ (MW 380.45); massspectroscopy (MH⁺) 381.3. Anal Calcd for C₂₁H₂₄N₄O₃; C, 66.30; H, 6.36;N, 14.73; Found: C, 66.14; H, 6.58; N, 14.49.

Example 5-48 Preparation of5-(R/S)-(N′-(2-Hydroxy-2-phenylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-D1) above using5-(R/S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 2-(R/S)-amino-1-phenylethanol (Sigma) thetitle compound was prepared. The final product was purified by flashchromatography (5% CH3OH in 2:1 CH2Cl2:EtAc) to give a mixture ofdiastereomers.

C27H28N4O4 (MW=472.54), mass spectroscopy (MH+) 473. Anal. Calcd forC27H28N4O4, C, 68.63, H, 5.97, N, 11.86. Found C, 68.14, H, 5.98, N,11.50.

Example 5-49 Preparation of5-(S)-(N′-((Hexylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-B1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and hexyl isocyanate (Aldrich) the titlecompound was prepared.

C25H32N4O3 (MW=436.56); mass spectroscopy (MH+) 437. Retention time;11.0 minutes.

Example 5-50 Preparation of5-(S)-(N′-((Cyclohexylaminocarbonyl)-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-B1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and cyclohexyl isocyanate (Aldrich) the titlecompound was prepared.

C25H30N4O3 (MW=434.54); mass spectroscopy (MH+) 435. Retention time; 8.2minutes.

Example 5-51 Preparation of5-(S)-(N′-((Isopropylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-B1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and isopropyl isocyanate (Aldrich) the titlecompound was prepared.

C22H26N4O3 (MW=394.48); mass spectroscopy (MH+) 395. Retention time; 5.3minutes.

Example 5-52 Preparation of5-(S)-(N′-((tert-Butylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-B1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and tert-butyl isocyanate (Aldrich) the titlecompound was prepared.

C23H28N4O3 (MW=408.50); mass spectroscopy (MH+) (409). Retention time;6.9 minutes.

Example 5-53 Preparation of5-(S)-(N′-((1-Adamantylaminocarbonyl]-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-B1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 1-adamantyl isocyanate (Aldrich) thetitle compound was prepared.

C29H34N4O3 (MW=486.62); mass spectroscopy (MH+) 487. Retention time;20.3 minutes.

Example 5-54 Preparation of5-(S)-(N′-((2-Methylpropylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and isobutylamine (Aldrich) the titlecompound was prepared.

C23H28N4O3 (MW=408.50); mass spectroscopy (MH+) 409. HPLC retentiontime: 6.592 minutes.

Example 5-55 Preparation of5-(S)-(N′-(R/S)-3-Hydroxy-3-phenylethylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 2-(R/S)-amino-1-phenylethanol (Sigma) thetitle compound was prepared.

C27H28N4O4 (MW=472.55); mass spectroscopy (MH+) 473. HPLC retentiontime: 5.707 minutes.

Example 5-56 Preparation of5-(S)-(N′-((3-Methybutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-[L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and isoamylamine (Aldrich) the title compoundwas prepared.

C24H30N4O3 (MW=422.53); mass spectroscopy (MH+) 423. HPLC retentiontime: 8.575 minutes.

Example 5-57 Preparation of5-(S)-((N′-(S)-1-Hydroxymethyl-3-methylbutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-D1) above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and (S)-leucinol (Aldrich) the title compoundwas prepared.

C25H32N4O4 (MW 452.56); mass spectroscopy (MH+) 453. Anal. Calcd forC25H32N4O4; C, 66.35, H, 7.13, N, 12.38. Found: C, 66.02, H, 7.03, N,11.84.

Example 5-58 Preparation of5-(S)-((N′-(1S)-(2S)-1-Hydroxymethyl-2-methylbutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-D1) above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and (L)-isoleucinol (Aldrich) the titlecompound was prepared.

C25H32N4O4 (MW=452.56); mass spectroscopy (MH+) 453. Anal. Calcd forC25H32N4O4; C, 66.35, H, 7.13, N 12.38. Found: C, 66.31, H, 6.93, N,12.21.

Example 5-59 Preparation of5-(S)-(N′-(3-Chloropropylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-B1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 3-chloropropyl isocyanate (Aldrich) thetitle compound was prepared.

C22H₂₅ClN4O3 (MW 428.92); mass spectroscopy (MH+) 429. Retention time;6.0 minutes.

Example 5-60 Preparation of5-(S)-(N′-Octylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-B1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and octyl isocyanate (Aldrich) the titlecompound was prepared.

C27H36N4O3 (MW=464.61); mass spectroscopy (MH+) 465. Retention time;29.7 minutes.

Example 5-61 Preparation of5-(S)-(N′-1,1,3,3-Tetramethylbutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-B1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 1,1,3,3-tetramethylbutyl isocyanate(Aldrich) the title compound was prepared.

C27H36N4O3 (MW=464.61); mass spectroscopy (MH+) 465. Retention time;20.3 minutes.

Example 5-62 Preparation of5-(S)-(N′-(R/S)-1-Methylbutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 1-(R/S)-methylbutylamine (Aldrich) thetitle compound was prepared.

C24H30N4O3 (MW=422.53); mass spectroscopy (MH+) 423. HPLC retentiontime: 8.0 minutes.

Example 5-63 Preparation of5-(S)-((N′-(R/S)-1-Hydroxymethylbutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 2-(R/S)-amino-1-pentanol (Aldrich) thetitle compound was prepared.

C24H30N4O4 (MW=438.53); mass spectroscopy (MH+) 439. HPLC retentiontime: 4.6 minutes.

Example 5-64 Preparation of5-(S)-((N′-(R/S)-1,3-Dimethylbutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and (R/S)-1,3-dimethylbutylamine (Aldrich)the title compound was prepared.

C25H32N4O3 (MW=436.56); mass spectroscopy (MH+) 437. HPLC retentiontime: 10.6 minutes.

Example 5-65 Preparation of5-(S)-((N′-(R)-1-Hydroxymethyl-3-metylbutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and (R)-Leucinol (Aldrich) the title compoundwas prepared.

C25H32N4O4 (MW=452.56); mass spectroscopy (MH+) 453. HPLC retentiontime: 5.0 minutes.

Example 5-66 Preparation of5-(S)-((N′-(R/S)-2-Methylbutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 2-(R/S)-methylbutylamine (Aldrich) thetitle compound was prepared.

C24H30N4O3 (MW=422.53); mass spectroscopy (MH+) 423. HPLC retentiontime: 8.1 minutes.

Example 5-67 Preparation of5-(S)-(N′-Morpholinoaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and morpholine (Aldrich) the title compoundwas prepared.

C23H26N4O4 (MW=422.48); mass spectroscopy (MH⁺) 423. Retention time; 4.5minutes.

Example 5-68 Preparation of5-(S)-(N′-(2-(2-Hydroxyethoxy)-ethylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 2-(2-aminoethoxy)ethanol (Aldrich) thetitle compound was prepared.

C23H28N4O5 (MW=440.50); mass spectroscopy (MH+) 441. Retention time; 3.8minutes.

Example 5-69 Preparation of 5-(S)-(N-Piperidinylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B), piperidine (Aldrich), anddiisopropylethylamine (Aldrich) (1.5 eq) the title compound wasprepared.

C24H28N4O3 (MW=420.51); mass spectroscopy (MH+) 421. Retention time; 6.9minutes.

Example 5-70 Preparation of5-(S)-(N′-(N″-methyl-N″-Butylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and N-methyl-butylamine (Aldrich) the titlecompound was prepared.

C24H30N4O3 (MW 422.53); mass spectroscopy (MH+) 423. Retention time; 8.8minutes.

Example 5-71 Preparation of5-(S)-(N′-(1-(R/S)-Hydroxymethylcyclopentylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 1-aminocyclopentane methanol (Aldrich)the title compound was prepared.

C25H30N4O4 (MW=450.54); mass spectroscopy (MH+) 451. Retention time; 5.3minutes.

Example 5-72 Preparation of5-(S)-(N′-(4-Hydroxybutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 4-aminobutanol (Aldrich) the titlecompound was prepared.

C23H28N4O4 (MW=424.50); mass spectroscopy (MH+) 425. Retention time; 3.9minutes.

Example 5-73 Preparation of5-(S)-(N′-(1-(R/S)-Hydroxymethyl-2-methylpropylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 2-amino-3-methylbutanol (Aldrich) thetitle compound was prepared.

C24H30N4O4 (MW=438.53); mass spectroscopy (MH+) 439. Retention time; 4.7minutes.

Example 5-74 Preparation of5-(S)-(N′-(2-(R/S)-Hydroxycyclohexylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B), 2-aminocyclohexanol (Janssen), anddiisopropylethylamine (Aldrich) (1.5 eq) the title compound wasprepared.

C25H30N4O4 (MW=450.54); mass spectroscopy (MH+) 451. Retention time; 4.9minutes.

Example 5-75 Preparation of5-(S)-(N′-(Isopropyl-hydroxyaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-D1) above using5-(R/S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and N-isopropylhydroxylamine hydrochloride(Aldrich), in the presence of diisopropylethylamine (Aldrich) the titlecompound was prepared. The final product was purified by flashchromatography (ethyl acetate) to give a mixture of diastereomers.

C22H26N4O4 (MW=410.471), mass spectroscopy (MH+) 411. 1H NMR (CD3OD, 400MHz, d) 7.64-7.36 (m, 8H), 5.17 (s, 1H), 4.48-4.38 (m, 1H), 4.354.25 (m,1H), 3.29 (s, 3H), 1.40 (d, J=7.3 Hz, 3H), 1.12-1.09 (m, 6H).

Example 5-76 Preparation of5-(S)-(N′-(Benzyl-hydroxyaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-D1) above using5-(R/S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and N-benzylhydroxylamine hydrochloride(Aldrich), in the presence of diisopropylethylamine (Aldrich) the titlecompound was prepared. The final product was purified by flashchromatography (ethyl acetate) to yield a mixture of diastereomers.

C26H26N4O4 (MW=458.52), mass spectroscopy (MH+) 459. 1H NMR (CD3OD, 400MHz, d) 7.65-7.12 (m, 13H), 5.19 (s, 1H), 4.70-4.58 (m, 2H), 4.51-4.44(m, 1H), 3.32 (s, 3H), 1.44-1.41 (m, 3H).

Example 5-77 Preparation of5-(S)-(N′-(Thiomorpholinylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and thiomorpholine (Aldrich) the titlecompound was prepared.

C23H26N4O3S (MW=438.55); mass spectroscopy (MH+) 439. Retention time;5.9 minutes.

Example 5-78 Preparation of5-(S)-(N′-(2(R/S)-Hydroxybutylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 2-(R/S)-hydroxybutylamine (Transworld)the title compound was prepared.

C23H28N4O4 (MW=424.50); mass spectroscopy (MH+) 425. Retention time; 4.2minutes.

Example 5-79 Preparation of5-(S)-(N′-2,2,2-Trifluoroethylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 2,2,2-triflouroethylamine (Aldrich) thetitle compound was prepared.

C21H21F3N4O3 (MW=434.42); mass spectroscopy (MH+) 435. Retention time;6.0 minutes.

Example 5-80 Preparation of5-(S)-(N′-(4R/S)-Cyclohexylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and 4-aminocyclohexanol (Fluka) the titlecompound was prepared.

C25H30N4O4 (MW=450.54); mass spectroscopy (MH+) 451. Retention time; 4.0minutes.

Example 5-81 Preparation of5-(S)-(N′-(1R)-Hydroxymethyl-3-methylthiopropylaminocarbonyl)-L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure (5-C1) above using5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and L-methioninol (Lancaster) the titlecompound was prepared.

C24H30N4O4S (MW=470.60); mass spectroscopy (MH+) 471. Retention time;4.6 minutes.

Example 6-1 Preparation of5-{N′-(Benzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

To 5-(L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) (0.1500 g, 0.434 mmol) in THF (4 ml) wereadded pyridine (0.088ml, 1.09 mmol) and benzenesulfonyl chloride(Aldrich) (0.061 ml, 0.477 mmol), stirred at RT for 2 days. The reactionmixture was evaporated to dryness. Water and CH₂Cl₂ were added. CH₂Cl₂layer was dried over MgSO₄. Evaporation and flash chromatography(silica, 5-6% MeOH/CH₂Cl₂) gave a residue, which was crystallized inCHCl₃/hexane and washed with Et₂O to give the title compound (0.027 g,14%) as a white solid.

C24H₂₃N3O4S (MW=449.529); mass spectroscopy (MH⁺) 448. Anal. Calcd forC24H₂₃N3O4S: C, 64.13; H, 5.16; N, 9.35; Found: C, 63.99; H, 5.05; N,9.24.

Example 6-2 Preparation of5-{N′-(3-Fluorobenzenesulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) (0.1500 g, 0.434 mmol) in THF (4 ml) wasadded pyridine (0.088ml, 1.09 mmol) and 3-fluorobenzenesulfonyl chloride(Fluorochem Limited) (0.0928 ml, 0.477 mmol), stirred at RT overnight.The reaction mixture was evaporated to dryness. Water was added,filtered. The solid was purified with flash chromatography (silica, 6%MeOH/CH₂Cl₂, crystallized with CH₂Cl₂/hexane and washed with Et₂O/hexane(1:1, v/v) to give the title compound (0.0580 g, 29%) as a white solid.

C24H22FN3O4S (MW=467.519); mass spectroscopy (MH⁺) 468. Anal. Calcd forC24H22FN3O4S: C, 61.66; H, 4.74; N, 8.99; Found: C, 61.76; H, 4.93; N,8.76.

Example 6-3 Preparation of5-{N′-(benzylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6one

To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7B) (0.2050 g, 0.66 mmol) in DMF (5 ml) was addedbenzylsulfonyl chloride (Aldrich) (0.0632 g, 0.33 mmol), stirred at RTfor 3.5 days. The reaction mixture was evaporated to dryness. Water wasadded, extracted with CH₂Cl₂, washed with brine, dried over MgSO₄.Evaporation and flash chromatography (silica, 5% MeOH /CH₂Cl₂), gave aresidue, which was washed with Et₂O /hexane (1:2, v/v) to give the titlecompound (0.0531 g, 35%) as a light yellow solid.

C25H₂₅N3O4S (MW=463.555); mass spectroscopy (MH⁺) 464. Anal. Calcd forC25H₂₅N3O4S: C, 64.78; H, 5.44; N, 9.06; Found: C, 64.83; H, 5.17; N,8.86.

Example 6-4 Preparation of5-{N′-(Butylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6one

To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added pyridine(0.059 ml, 0.728 mmol) and 1-butanesulfonyl chloride (Aldrich) (0.063ml, 0.485 mmol), stirred at RT overnight. The reaction mixture wasevaporated to dryness. Water was added, extracted with EtOAc, washedwith brine, dried over MgSO₄. Evaporation and flash chromatography(silica, 5% MeOH/CH₂Cl₂), gave the title compound (0.0714 g, 34%) as ayellow solid.

C22H27N3O4S (MW=429.538); mass spectroscopy (MH⁺) 430. Anal. Calcd forC22H27N3O4S: C, 61.52; H, 6.34; N, 9.78; Found: C, 61.78; H, 6.40; N,9.51.

Example 6-5 Preparation of5-{N′-(Octylsulfonyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added pyridine(0.059 ml, 0.728 mmol) and 1-octanesulfonyl chloride (Aldrich) (0.095ml, 0.485 mmol), stirred at RT overnight. The reaction mixture wasevaporated to dryness. Water was added, extracted with EtOAc, washedwith brine, dried over MgSO₄. Evaporation and flash chromatography(silica, 5% MeOH/CH₂Cl₂), gave the title compound (0.0805 g, 34%) as ayellow solid.

C26H35N3O4S (MW=485.646); mass spectroscopy (MH⁺) 486. Anal. Calcd forC26H35N3O4S : C, 64.30; H, 7.26; N, 8.65; Found: C, 64.14; H, 7.13; N,8,48.

Example 7-1 Preparation of5-(S)-(N′-(3,5-Difluorophenyl-α-aminoacetyl)-L-valinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above usingN-boc-3,5-difluorophenylglycine and5-(S)-(L-valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B), the protected intermediate was prepared as acolorless oil. The Boc-group was removed using 5.0 M HCl in dioxane andthe resulting free-base purified by flash chromatography using 98:2CHCl₃/MeOH yielding the title compound.

NMR data was as follows:

¹H-nmr (CDCl₃): delta=7.78 (d, 1H), 7.53-7.25 (m, 8H), 6.86 (m, 2H),6.71 (m, 2H), 5.22 (d, 1H), 4.76 (s, 1H), 4.43 (m, 1H), 3.34 (s, 3H),2.08 (m, 1H), 0.91 (m, 6H). C₂₈H₂₈F₂N₄O₃ (MW=506); mass spectroscopy(MH⁺) 506.9; Anal Calcd for C₂₈H₂₈F₂N₄O₃; C, 66.39; H, 5.57, N, 11.06;Found: C, 66.33; H, 5.67; N, 10.89.

Example 7-2 Preparation of5-(S)-(N′-(3,5-Difluorophenyl-α-aminoacetyl)-L-tert-leucinyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above usingN-boc-3,5-difluorophenylglycine and5-(S)-(L-tert-leucinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride, the protected intermediate was prepared as a colorlessoil. The Boc-group was removed using 5.0 M HCl in dioxane and theresulting free-base purified by flash chromatography using 98:2CHCl₃/MeOH yielding the title compound.

C₂₉H₃₀F₂N₃O₄ (MW=520.57); mass spectroscopy (MH⁺) 521; Anal Calcd forC₂₉H₃₀F₂N₃O₄; C, 66.91; H, 5.81, N, 10.76; Found: C, 66.66; H, 5.70; N,10.55.

Example 7-3 Preparation of5-(S)-(N′-(Valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and L-Boc-Valine (Aldrich), the protectedintermediate was prepared. This was purified by flash chromatographyusing CHCl₃/MeOH (99: 1). The Boc-group was removed using 5.0 M HCl indioxane and the resulting free-base purified by flash chromatographyCHCl3/MeOH (95:5) yielding the title compound.

C23H28N4O3 (MW=408.499); mass spectroscopy (MH⁺) 409. Anal. Calcd forC23H28N4O3; C, 67.63; H, 6.91; N, 13.72. Found: C, 67.48; H, 7.01; N,13.70.

Example 7-4 Preparation of5-(S)-(N′-(Phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure F above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and the acid fluoride of L-Boc-phenylglycine(Carpino, et. al., J. Org. Chem., (1991), 56, 2611-2614), the protectedintermediate was prepared. This was purified by flash chromatographyusing CHCl₃/MeOH (99:1). The Boc-group was removed using 5.0 M HCl indioxane and the resulting hydrochloride purified by flash chromatographyCHCl₃/MeOH (99:1) yielding the title compound.

C26H26N4O3 (MW=442.516); mass spectroscopy (MH+) 443. Anal. Calcd forC26H26N4O3.HCl; C, 65.79; H, 5.68; N, 11.69. Found: C, 65.69; H, 5.63;N, 11.42.

Example 7-5 AND 7-6 Preparation of 5-(S)-(N′-(R andS)-3,5-Difluorophenyl-α-aminoacetyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and D/L-Boc-3,5-difluorophenylglycine, theprotected intermediate was prepared. The Boc-group was removed using 5.0M HCl in dioxane and the resulting free-base diastereomers were purifiedby flash chromatography CHCl₃/MeOH (98:2) yielding the title compounds.

Isomer A: C26H24F2N4O3 (MW=478.497); mass spectroscopy (MH+) 479. Anal.Calcd for C26H24F2N4O3. 0.6681 mol H2O; C, 63.66; H, 5.20; N, 11.42.Found: C, 63.65; H, 5.35; N, 11.56.

Isomer B: C26H24F2N4O3 (MW=478.497); mass spectroscopy (MH+) 479. Anal.Calcd for C26H24F2N4O3. 0.5146 mol H2O; C, 64.02; H, 5.17N, 11.49.Found: C, 64.04; H, 5.01; N, 11.30.

Example 7-8 Preparation of5-(S)-(N′-(D-Valinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and D-Boc-Valine (Aldrich), the protectedintermediate was prepared. This was purified by flash chromatographyusing CHCl₃/MeOH (99:1). The Boc-group was removed using 5.0 M HCl indioxane and the resulting free-base purified by flash chromatographyCHCl₃/MeOH (95:5) yielding the title compound.

C23H28N4O3 (MW=408.499); mass spectroscopy (MH+) 409. Anal. Calcd forC23H28N4O3; C, 67.63; H, 6.91; N, 13.72. Found: C, 68.18; H, 6.88; N,13.79.

Example 7-9 Preparation of5-(S)-(N′-(D-Phenylglycinyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-B) and D-boc-phenylglycine (Aldrich), theprotected intermediate was prepared. The Boc-group was removed using 5.0M HCl in dioxane and the resulting free-base purified by flashchromatography CHCl₃/MeOH (95:5) yielding the title compound.

C26H26N4O3 (MW=442.516); mass spectroscopy (MH+) 443. Anal. Calcd forC26H26N4O3; C, 70.57; H, 5.92; N, 12.66. Found: C, 70.39; H, 5.93; N,12.43.

Example 7-10 Preparation of5-(S)-(N′-(3,5-Difluorophenyl-α-aminoacetyl)-L-alaninyl-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-B) and N-boc-3,5-difluorophenylglycine, theprotected intermediate was prepared. The Boc-group was removed using 5.0M HCl in dioxane and the resulting free-base purified by flashchromatography yielding the title compound. The molecular weight asdetermined by mass spectrometry (FD) was: (M+H).

Example 7-11 Synthesis of5-(S)-[N′-(L-Trifluoromethylphenylglycinyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and (S)-2-Phenyl-N-(trifluoroacetyl)glycine(Aldrich), the title compound was prepared. The product was purified byflash chromatography using CHCl3/MeOH (99:1).

C28H25F3N4O4 (MW=538.524); mass spectroscopy (MH+) 539. Anal. Calcd forC28H25F3N4O4; C, 62.45; H, 4.68; N, 10.40. Found: C, 62.33; H, 4.78; N,10.16.

Example 7-12 Synthesis of5-(S)-[N′-(L-N-Methyl-valinyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and L-N-Methyl-Boc-Valine (Aldrich), theprotected intermediate was prepared. This was purified by flashchromatography using CHCl3/MeOH (98:2). The Boc-group was removed using5.0 M HCl in dioxane and the resulting free-base purified by flashchromatography CHCl3/MeOH (98:2) yielding the title compound.

C24H30N4O3 (MW=422.526); mass spectroscopy (MH⁺) 423. Anal. Calcd forC24H30N4O3. 0.6269 mol H2O; C, 66.44; H, 7.26; N, 12.91. Found: C,66.50; H, 7.47; N, 12.70.

Example 7-13 Synthesis of5-(S)-[N′-(Hexafluorovalinyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and Boc-Hexafluorovaline (Aldrich), theprotected intermediate was prepared. This was purified by flashchromatography using CHCl3/MeOH (98:2). The Boc-group was removed using5.0 M HCl in dioxane and the resulting free-base purified by flashchromatography CHCl3/MeOH (97:3) yielding the title compound.

C23H22F6N4O3 (MW=516.44); mass spectroscopy (MH+) 517. Anal. Calcd forC23H22F6N4O3; C, 51.68 H, 4.49; N, 10.47. Found: C, 51.46; H, 4.22; N,9.94.

Example 7-15 Preparation of5-(S)-(N′-(L-Valinyl)-L-alaninyl-)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Following General Procedure D above using N-boc-L-valine and5-(S)-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-onehydrochloride (Example 8-B), the protected intermediate was prepared.The Boc-group was removed using 5.0 M HCl in dioxane and the resultingfree-base purified by flash chromatography yielding the title compound.Anal. Calc'd for C24H29N5O3:C, 66.19, H, 6.71; N, 16.08. Found: C:66.50; H, 6.68; N, 15.87. MS Found (M+H) 436.

Example 7-17 Preparation of5-(S)-(N″-(S)-Phenylglycinyl)-N′-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one

Step A—Preparation of3-[(N′″-t-Butoxycarbonyl)-N″-(S)-phenylglycinyl)-N′-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one

To a solution of3-[(N′-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one(Example 8M) (300 mg, 0.89 mmol) in THF (30 mL) was addedL-Boc-phenylglycine (246 mg, 0.98 mmol, NovaBioChem) and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (242 mg, 0.98 mmol,Aldrich). The resulting mixture was stirred at ambient temperature undernitrogen overnight. The mixture was diluted with EtOAc (500 mL) andwashed with water (1×100 mL) and brine (1×100 mL). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby HPLC eluting with hexanes/EtOAc (1:1) to yield the title intermediate(230 mg).

Step B—Synthesis of5-(S)-(N″-(S)-Phenylglycinyl)-N′-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one

Through a solution of the product from step A (230 mg, 0.40 mmol) in1,4-dioxane (50 mL) was passed a stream of HCl gas for 10 minutes. Theresulting solution was capped and stirred overnight at ambienttemperature, then concentrated. The residue was dissolved in water (100mL) and washed with Et₂O (1×100 mL). Then, the aqueous layer wasbasified to pH 9 with 1 M aq. NaOH, and the product extracted into EtOAc(100 mL). The EtOAc extract was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by HPLC eluting with CH₂Cl₂/MeOH(95:5) to yield the title compound (114 mg) as a white solid.

C₂₇H₂₉N₅O₃ (MW=471.56) mass spectroscopy (MH⁺) 472.3, (MH⁻) 470.3; HRMS.Calcd. for C₂₇H₃₀N₅O₃: 472.2348. Found: 472.2352.

Example 7-18 Preparation of5-(S)-[(N″-L-Valinyl)-N′-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one

Step A—Synthesis of3-[(N′″-t-Butoxycarbonyl)-N′-(S)-valinyl)-N′-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one

To a solution of3-[(N′-L-alaninyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one(Example 8M) (300 mg, 0.89 mmol) in THF (30 mL) was added L-Boc-valine(212 mg, 0.98 mmol, NovaBioChem) and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (242 mg, 0.98 mmol,Aldrich). The resulting mixture was stirred at ambient temperature undernitrogen overnight. The mixture was diluted with EtOAc (500 mL) andwashed with water (1×100 mL) and brine (1×100 mL). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby HPLC eluting with hexanes/EtOAc (1:1) to yield the title intermediate(240 mg).

Step B—Synthesis of5-(S)-(N′-L-Alaninyl-N″-L-valinyl]amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one

Through a solution of the product from step A (240 mg, 0.44 mmol) in1,4-dioxane (50 mL) was passed a stream of HCl gas for 10 minutes. Theresulting solution was capped and stirred overnight at ambienttemperature, then concentrated. The residue was dissolved in water (100mL) and washed with Et₂O (1×100 mL). Then, the aqueous layer wasbasified to pH 9 with 1 M aq. NaOH, and the product extracted into EtOAc(100 mL). The EtOAc extract was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by HPLC eluting with CH₂Cl₂/MeOH(95:5) to yield the title compound (180 mg) as a white solid.

C₂₄H₃₁N₅O₃ (MW 437.54) mass spectroscopy (MH⁺) 438.2, (MH⁻) 436.5; HRMS.Calcd. for C₂₄H₃₁N₅O₃: 438.2505. Found: 438.2502.

ExampleS 7-19 AND 7-20 Preparation of3-(N″-(3,5-Difluorophenylglycinyl)-N′-L-alaninyl]amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepineHydrochloride

Step A—Preparation of3-[((N′″-t-butoxycarbonyl)-N″-(3,5-difluorophenylglycinyl)-N′-L-alaninyl]amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepineHydrochloride

To a solution of3-(N′-L-alaninyl)-amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepine(Example 8-N) (500 mg, 1.28 mmol) in THF (15 mL) was addedN-t-boc-D,L-3,5-difluorophenylglycine (404 mg, 1.41 mmol),1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (270 mg,1.41 mmol), 1-hydroxybenzotriazole hydrate (190 mg, 1.41 mmol), followedby N,N-diisopropylethylamine (490 μL, 2.82 mmol).

The resulting mixture was stirred at ambient temperature under nitrogenovernight. The mixture was diluted with EtOAc (200 mL) and washed withwater (1×200 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by HPLC eluting withhexanes/EtOAc (1:1) to yield the title intermediate as two separateddiastereomers (labeled isomer 1 as the less polar intermediate (280 mg),and isomer 2 as the more polar intermediate (316 mg)).

Data for isomer 1:

C₃₂H₃₃N₅O₆F₂ (MW 621.64) mass spectroscopy (MH⁺) 622.5, (MH⁻) 620.7;Anal. Calcd. for C₃₂H₃₃N₅O₆F₂: C, 61.83; H, 5.35; N, 11.27. Found: C,61.58; H, 5.23; N, 10.97.

Data for isomer 2:

C₃₂H₃₃N₅O₆F₂ (MW 621.64) mass spectroscopy (MH⁺) 622.5, (MH⁻) 620.7;Anal. Calcd. for C₃₂H₃₃N₅O₆F₂: C, 61.83; H, 5.35; N, 11.27. Found: C,61.95; H, 5.24; N, 10.98.

Step B—Preparation of3-[(N″-(3,5-Difluorophenylglycinyl)-N′-L-alaninyl]amino-2,4dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-2H-1,5-benzodiazepineHydrochloride

Through a solution of isomer 1 from step A (250 mg, 0.40 mmol) in1,4-dioxane (80 mL) was passed a stream of HCl gas for 5 minutes. Theresulting solution was capped and stirred overnight at ambienttemperature, then concentrated. The title compound was isolated (161 mg)as a white solid by trituration with hexanes/EtOAc.

Data for the title compound from isomer 1:

C₂₇H₂₅N₅O₄F₂ HCl (FW 557.98) mass spectroscopy (MH⁺, —HCl) 523.4, (MH⁻,—HCl) 520.3; HRMS. Calcd. for C₂₇H₂₆N₅O₄F₂: 522.1953. Found: 522.1949.Optical rotation: [ ]²⁰ _(D)=73.02 (c 0.5, MeOH); m.p. 218-219 C.

Isomer 2 (280 mg, 0.45 mmol) was processed in the same manner as isomer1, except using 90 mL of 1,4-dioxane. Yielding 200 mg of the titlecompound as a white solid.

Data for the title compound from isomer 2:

C₂₇H₂₅N₅O₄F₂ HCl (FW 557.98) mass spectroscopy (MH⁺, —HCl) 523.4, (MH⁻,—HCl) 520.3; HRMS. Calcd. for C₂₇H₂₆N₅O₄F₂: 522.1953. Found: 522.1959.Optical rotation: [ ]²⁰ _(D)=134.28 (c 0.5, MeOH). m.p. at 184 C thewhite solid became a foam.

Example 7-21 Preparation of5-(S)-[N′-(2-Amino-3,3,3-trifluoromethylbutyryl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and D/L-Boc4,4,4-trifluorovaline (Oakwood),the protected intermediate was prepared. This was purified by flashchromatography using CHCl₃/MeOH (99:1). The Boc-group was removed using5.0 M HCl in dioxane and the resulting free-base purified by flashchromatography CHCl₃/MeOH (98:2) yielding the title compounds.

Isomer 1:

C₂₃H₂₅F₃N₄O₃ (MW=462.47); mass spectroscopy (MH+) 463. Anal. Calcd forC₂₃H₂₅F₃N₄O₃.0.95 mol H₂O; C, 57.59; H, 5.65; N, 11.62. Found: C, 57.64;H, 5.77; N, 11.52.

Isomer 2:

C₂₃H₂₅F₃N₄O₃ (MW=462.47); mass spectroscopy (MH+) 463. Anal. Calcd forC₂₃H₂₅F₃N₄O₃.0.91 mol H₂O; C, 57.67; H, 5.65; N, 11.70. Found: C, 57.69;H, 5.65; N, 11.40.

Example 7-22 Preparation of 5-(S)-[N′-(2-Amino-5,5,5-trifluoropentanyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-1-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) and D/L-Boc-5,5,5-trifluoronorvaline(Oakwood), the protected intermediate was prepared. This was purified byflash chromatography using CHCl₃/MeOH (9:1). The Boc-group was removedusing 5.0 M HCl in dioxane and the resulting free-base purified by flashchromatography CHCl₃/MeOH (95:5) yielding the title compounds.

Isomer 1:

C₂₃H₂₅F₃N₄O₃ (MW=462.47); mass spectroscopy (MH+) 463. Anal. Calcd forC₂₃H₂₅F₃N₄O₃.0.4295 mol H₂O; C, 58.75; H, 5.54; N, 11.91. Found: C,58.81H, 5.38; N, 11.53.

Isomer 2:

C₂₃H₂₅F₃N₄O₃ (MW=462.47); mass spectroscopy (MH+) 463. Anal. Calcd forC₂₃H₂₅F₃N₄O₃.0.2318 mol H₂O; C, 59.19; H, 5.50; N, 12.00. Found: C,59.27; H, 5.55; N, 11.67.

Example 7-23 Preparation of5-(S)-[N′-(2-Amino-4,4,4trifluorobutyryl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D above using5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7B) andD/L-(2-N-Boc-amino)-4,4,4-trifluorobutyric acid (Oakwood), the protectedintermediate was prepared. The Boc-group was removed using 5.0 M HCl indioxane and the resulting free-base purified by flash chromatographyCHCl₃/MeOH (95.5) yielding the title compounds.

Isomer 1:

C₂₂H₂₃F₃N₄O₃ (MW=448.443); mass spectroscopy (MH+) 449. Anal. Calcd forC₂₂H₂₃F₃N₄O₃. 0.7377 mol H₂O; C, 57.23; H, 5.34; N, 12.13. Found: C,57.27; H, 5.13; N, 11.82.

Isomer 2:

C₂₂H₂₃F₃N₄O₃ (MW=448.443); mass spectroscopy (MH+) 449. Anal. Calcd forC₂₂H₂₃F₃N₄O₃. 0.6657 mol H₂O; C, 57.39; H, 5.32; N, 12.17. Found: C,57.42; H, 5.19; N, 11.95.

Example 7-24 Preparation of 1-(S)-[N-(2-Amino-3,3,3-trifluorobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

Following General Procedure D above using1-(S)-[L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-onehydrochloride (Example 7-30, below) and D/L-N-Boc-4,4,4-trifluorovaline(Oakwood), the protected intermediate was prepared. This was purified byflash chromatography using CHCl₃/MeOH (99:1). The Boc-group was removedusing 5.0 M HCl in dioxane and the resulting free-base purified by flashchromatography CHCl₃/MeOH (95:5) yielding the title compounds.

Isomer 1(single diastereomer):

C₁₉H₂₅F₃N₄O₃ (MW=414.426); mass spectroscopy (MH+) 415; Anal. Calcd forC₁₉H₂₅F₃N₄O₃; C, 55.07; H, 6.08; N, 13.52. Found: C, 55.18; H, 6.11; N,13.49.

Isomer 2(single diastereomer):

C₁₉H₂₅F₃N₄O₃ (MW=414.426); mass spectroscopy (MH+) 415; Anal. Calcd forC₁₉H₂₅F₃N₄O₃; C, 55.07; H, 6.08; N, 13.52. Found: C, 54.82; H, 6.06; N,13.35.

Isomer 3(mixture of two diastereomers):

C₁₉H₂₅F₃N₄O₃ (MW=414.426); mass spectroscopy (MH+) 415; Anal. Calcd forC,9H₂₁F₃N₄O₃; 0.255 mol H₂O C, 54.46; H, 6.14; N, 13.37. Found: C,54.54; H, 6.14; N, 13.05.

Example 7-25 Preparation of1-(S)-[N′-(2-Amino-5,5,5-trifluoropentanoyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

Following General Procedure D above using1-(S)-[L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-onehydrochloride (Example 7-30, below) andD/L-N-Boc-5,5,5-trifluoronorvaline (Oakwood), the protected intermediatewas prepared. The Boc-group was removed using 5.0 M HCl in dioxane andthe resulting free-base purified by flash chromatography CHCl₃/MeOH(95:5) yielding the title compounds.

Isomer 1(single diastereomer):

C₁₉H₂₅F₃N₄O₃ (MW 414.1967); High resolution MS (MH+) 415.1957; 400 MHZ¹H NMR (CDCl₃) d=6.17 ppm (d, 1H), 4.61 (m, 1H), 3.01 (s, 3H), 1.49 (d,3H).

Isomer 2(single diastereomer):

C₁₉H₂₅F₃N₄O₃ (MW=414.1967); High resolution MS (MH+) 415.1946; 400 MHZ¹H NMR (CDCl₃) d=6.18 ppm (d, 1H), 4.64 (m, 1H), 3.01 (s, 3H), 1.48 (d,3H).

Example 7-26 Preparation of1-(S)-[N′-(2-Amino-4,4,4-trifluorobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

Following General Procedure D above using1-(S)-[L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-onehydrochloride (Example 7-30, below) and2-(N-Boc-amino)-4,4,4-trifluorobutyric acid (Oakwood), the protectedintermediate was prepared. The Boc-group was removed using 5.0 M HCl indioxane and the resulting free-base purified by flash chromatographyCHCl₃/MeOH (97.3) yielding the title compounds.

Isomer 1(single diastereomer):

C₁₈H₂₃F₃N₄O₃ (MW=400.399); mass spectroscopy (MH+) 401; Anal. Calcd forC₁₈H₂₃F₃N₄O₃; C, 53.99; H, 5.79N, 13.99 Found: C, 54.08; H, 5.90; N,13.70.

Isomer 2 (single diastereomer):

C₁₈H₂₃F₃N₄O₃ (MW 400.399); high resolution MS (MH+) 401.1800; 400 MHZ ¹HNMR (CDCl₃) d=6.18 ppm (d, 1H), 4.61 (m, 1H), 3.01 (s, 3H), 2.22 (m,2H), 1.48 (d, 3H).

Example 7-27 Preparation of1-(S)-N′-(2-Aminobutyryl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

Following General Procedure D above using1-(S)-[L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-onehydrochloride (Example 7-30, below) and 2-(L-N-Boc-amino)butyric acid(Aldrich), the protected intermediate was prepared. The Boc-group wasremoved using 5.0 M HCl in dioxane and the resulting free-base purifiedby chromatography CHCl₃/MeOH (95:5) yielding the title compound.

C₁₈H₂₆N₄O₃ (MW=346.428); mass spectroscopy (MH+) 347; Anal. Calcd forC₁₈H₂₆N₄O₃; C, 62.41; H, 7.56; N, 16.17 Found: C, 62.46; H, 7.73; N,15.98.

Example 7-28 Preparation of1-(S)-[N′-(Hexafluorovalinyl)-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

Following General Procedure D above using1-(S)-[L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-onehydrochloride (Example 7-30, below) and N-Boc-hexafluorovaline(Aldrich), the protected intermediate was prepared. The Boc-group wasremoved using 5.0 M HCl in dioxane and the resulting free-base purifiedby chromatography CHCl₃/MeOH (95:5) yielding the title compound as amixture of diastereomers.

C₁₉H₂₂F₆N₄O₃ (MW=468.396); mass spectroscopy (MH+) 469; Anal. Calcd forC₁₉H₂₂F₆N₄O₃; C, 48.72; H, 4.73; N, 11.96 Found: C, 48.56; H, 4.73; N,11.83.

Example 7-29 Preparation of1-(S)-[N′-(L-2-Aminobutyryl)-L-alaninyl]-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

Following General Procedure D above using1-(S)-[L-alaninyl]-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-onehydrochloride (Example 7-31, below) and L-2-(N-Boc)-aminobutyric acid(Aldrich), the protected intermediate was prepared. The Boc-group wasremoved using 5.0 M HCl in dioxane and the resulting free-base purifiedby chromatography CHCl₃/MeOH (95:5) yielding the title compound as amixture of diastereomers.

C₂₁H₃₂N₄O₃ (MW 388.509); mass spectroscopy (MH+) 389; Anal. Calcd forC₂₁H₃₂N₄O₃; C, 64.92; H, 8.30; N, 14.42 Found: C, 64.62; H, 8.12; N,14.29.

Example 7-30 Preparation of1-(S)-[L-Alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-oneHydrochloride

Step A: Synthesis of1-Hydroxyimino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one

Following the procedure described for Example 7-A (Step B) and using3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one (CS# 73644-95-8),1-hydroxyimino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one wasprepared.

C₁₁H₁₂N₂O₂(MW=204.1); mass spectroscopy (MH+) 205.

Step B: Synthesis of(R/S)-1-Amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one.

The compound isolated above was reduced following General Procedure 7-A(Step C),(R/S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one wasprepared.

C₁₁H₁₄N₂O (MW=190.1); mass spectroscopy (MH+) 191.

Step C: Resolution of(S)-1-Amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one.

The amine isolated above was resolved as described in General Procedure7-C using Di-p-Toluoyl-L-tartaric acid (Aldrich, CAS# 32634-66-5).Enantiomeric excess (ee) was determined by Capillary Electrophoresisusing a Beckman Place MDQ and 5% sulfated α-cyclodrextrin, 20 mM(Et₃N)(NH₄)PO₄ (pH=2.5) on a 50 m capillary @ 15 kVolts and the detectorset at 20° C.m (200 nM). The desired enantiomer had a migration time of7.4 minutes relative to the undesired enantiomer (migration time=6.83minutes).

[a]=−72 (c=1, MeOH) as tartarate salt. ee=97%.

Step D: Synthesis of1-(S)-[N-t-Boc-L-alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one.

Using the amine isolated above and following the procedure described inExample 7-B (Step A) the title compound was isolated.

C₁₉H₂₇N₃O₄ (MW=362.19); mass spectroscopy (MH+) 362; Anal. Calcd forCl₁₉H₂₇N₃O₄; C, 63.14; H, 7.53; N, 11.62 Found: C, 63.01H, 7.44; N,11.59. [a]=+16.22 (c=1, CH₂Cl₂)

Step E: Synthesis of1-(S)-[L-Alaninyl]-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-onehydrochloride. The compound isolated above was treated as described inExample 7-B (Step B).

C₁₄H₁₉N₃O₂ HCl (MW=297.78); mass spec (MH+, free base) 262; Anal. Calcdfor C₁₄H₁₉N₃O₂ HCl; C, 56.47; H, 6.77; N, 14.11; Found: C, 56.27; H,6.56; N, 13.63. [a]=+38.99 (c=0.5, MeOH).

Example 7-31 Preparation of1-(S)-[L-Alaninyl]-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-oneHydrochloride

Step A: Synthesis of3-(2-Methylpropen-2-yl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one.

A solution of 4,5,6,7-tetrahydro-2H-3-benzazepin-2-one (61 g, 0.379 mol)in DMF was cooled to 0° C. and treated with a solution of LiHMDS (1.0 M,398 ml, 0.391 mols) over 30 minutes. Methallyl bromide (42 ml, 0.041mols) was added neat and the reaction allowed to stir for 2 hours at 0°C. under nitrogen atmosphere. Most of the solvent was removed underreduced pressure, the residue diluted into CH₂Cl₂ and washed with twoportions of 1.0 N HCl. The organics were washed 0.2 M LiCl, dried overNa₂SO₄ and chromatographed over SiO₂ using 9:1 CHCl₃/MeOH. Theappropriate fractions were pooled, evaporated to an oil which wasrecrystallized from hexanes/EtOAc yielding 17 g of a tan solid.

C₁₄H₁₇NO (MW=215); mass spectroscopy (MH+) 216. 400 MHZ ¹H NMR (CDCl₃)d=7.18-7.05 ppm (m, 4H), 4.88 (s, 1H), 4.79 (s, 1H), 3.98 (s, 2H), 3.93(s, 2H), 4.67 (m, 2H), 3.09 (m, 2H), 1.66 (s, 3H). Anal. Calcd forC₁₄H₁₇NO; C, 78.10; H, 7.97; N, 6.51 Found: C, 78.40; H, 8.08; N, 6.54.

Step B. Synthesis of3-(2-Methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one.

The compound isolated above was hydrogenated over 10% Pd/C at 35 psi ina Parr shaker for 2h at room temperature. The catalyst was filtered andthe titled compound isolated as a yellow oil.

C₁₄H₁₉NO (MW=217); mass spectroscopy (MH+) 218; Anal. Calcd forC₁₄H₁₉NO; C, 77.38; H, 8.81; N, 6.45; Found: C, 77.04; H, 8.81; N, 6.43.

Step C: Synthesis of1-Hydroxyimino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one.

Following the procedure described for Example 7-A (Step B) and using3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one,1-hydroxyimino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one wasprepared.

C₁₄H₁₈N₂O₂ (MW=246.3); mass spectroscopy (MH+) 247.

Step D: Synthesis of(R/S)-1-Amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one.

The compound isolated above was reduced following General Procedure 7-A(Step C),(R/S)-1-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-onewas prepared.

C₁₄H₂₀N₂O (MW=232.14); mass spectroscopy (MH+) 233.

Step E: Resolution of(S)-1-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one.

The amine isolated above was resolved as described in General Procedure7-C using Di-p-Toluoyl-L-tartaric acid (Aldrich, CAS# 32634-66-5).Enantiomeric excess (ee) was determined by Capillary Electrophoresisusing a Beckman Place MDQ and 5% sulfated a-cyclodrextrin, 20 mM(Et₃N)(NH₄)PO₄ (pH=2.5) on a 50 m capillary @ 15 kVolts and the detectorset at 20° C.m (200 nM). The desired enantiomer had a migration time of6.95 minutes relative to the undesired enantiomer (migration time=6.51minutes).

[a]=−78 (c=1, MeOH) as tartarate salt. ee=99%.

Step F: Synthesis of1-(S)-[N-t-boc-L-Alaninyl]-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one.

Using the amine isolated above and following the procedure described inExample 7-B (Step A) the title compound was isolated.

C₂₂H₃₃N₃O₄ (MW=4O3.52); mass spectroscopy (MH+) 404; Anal. Calcd forC₂₂H₃₃N₃O₄; C, 65.48; H, 8.24; N, 10.41; Found: C, 65.40; H, 7.99; N,10.66. [a]=−9.7 (c=0.5, MeOH).

Step G: Synthesis of1-(S)-[L-Alaninyl]-amino-3-(2-methylpropyl)-4,5,6,7-tetrahydro-2H-3-benzazepin-2-oneHydrochloride.

The compound isolated above was treated as described in Example 7-B(Step B).

C₁₇H₂₅N₃O₂ HCl (MW=339.864); mass spec (MH+, free base) 304; [a]=+29.5(c=1, MeOH).

Example 7-32 Synthesis of5-[N′-(S)-2-(4-Methylpentyl)amino-3-methylbutyryl-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Step A: Synthesis of5-[N′-(S)-2-tert-boc-Amino-3-methylbutyryl-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure D using N-tert-Boc-L-valine and (S)- and(R)-5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 3-B), the title compound was prepared.

C₂₈H₃₆N₄O₅ (MW=508.615); mass spectroscopy (MH⁺) 509.

Step B: Synthesis of5-[N′-(S)-2-Amino-3-methylbutyryl-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following General Procedure 4-N using the compound made above, the titlecompound was prepared after passing through an SCX column [5% MeOH(7NNH₃)/CH₂Cl₂].

C₂₃H₂₈N₄O₃ (MW=408.499); mass spectroscopy (MH⁺) 409.

Step C: Synthesis of5-[N′-(S)-2-(4-Methylpentyl)amino-3-methylbutyryl-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

To a solution of the compound made above (2.00 eq.) in MeOH was added afew drops of HCl-MeOH, 4-methyl-1-pentanal (1.00 eq.) (made by followingthe procedure described in Tetrahedron Letter, No.31, 1975, pp2647,incorporated herein by reference) and molecular sieves. NaBH₃CN (0.67eq.) was added. The pH of the reaction mixture was maintained at 5-6 byadding HCl-MeOH. The reaction mixture was stirred at RT overnight. Thereaction mixture was basified, extracted with EtOAc, dried over Na₂SO₄.Concentration and flash chromatography [silica gel, 5% MeOH (7 NNH₃)/CH₂Cl₂] gave the title compound.

C₂₉H₄₀N₄O₃ (MW=492.660); mass spectroscopy (MH⁺) 493. Anal. Calcd forC₂₉H₄₀N₄O₃: C, 70.70; H, 8.18; N, 11.37; Found: C, 70.92; H, 8.21; N,11.41.

Example 8-1 Preparation of3-[N′-3,5-Difluorophenyl-α-azidoacetyl)-L-alaninyl]-3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine

Following general procedure D using 3,5-difluorophenyl-α-azidoaceticacid and3-(L-alaninyl)-3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: (M+H).

Examples 9-1 and 9-2 Preparation of3-(S)-[2-((1H)-Isoquinoline-3,4-dihydro-3-oxo)-2-methyl-acetyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

Step A—Preparation of2-((1H)-Isoquinoline-3,4-dihydro-3-oxo)-2-methyl-acetic Acid Ethyl Ester

Through a solution of 3-isochromanone (1.00 g, 6.75 mmol, Aldrich) inabsolute EtOH (100 mL) was passed a stream of HBr gas for 10 minutes,during which time the temperature rose to 40° C. Alanine ethyl esterhydrochloride (1.036 g, 6.75 mmol, Aldrich) was then added and thereaction mixture heated to reflux for 2 hours. The mixture was allowedto cool, then concentrated. The residue was dissolved in absolute EtOH(100 ml), and K₂CO₃ (3.66 g, 27 mmol) was added and the mixture heatedto reflux for 18 hours. The mixture was allowed to cool, thenconcentrated. The residue was dissolved in EtOAc (200 mL) and washedwith water (1×100 mL). The organic phase was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by HPLC, elutingwith hexanes/EtOAc (1:1) to yield the title intermediate (204 mg).

C₁₄H₁₇N₁O₃ (MW 247.30) mass spectroscopy (MH⁺) 248.2, (MH⁻) 246.4; Anal.Calcd. for C₁₄H₁₇N₁O₃: C, 68.02; H, 6.88; N, 5.67. Found: C, 68.12; H,6.88; N, 5.40.

Step B—Preparation of2-((1H)-Isoquinoline-3,4-dihydro-3-oxo)-2-methyl-acetic Acid

To the intermediate from step A (170 mg, 9.688 mmol) in 1,4-dioxane (3mL) and water (1 mL) was added LiOH (57.7 mg, 1.38 mmol) and theresulting mixture was stirred at ambient temperature for 2.5 hours. Themixture was diluted into EtOAc (100 mL) and carboxylate extracted intowater (100 mL). The aqueous extract was acidified with 0.1 M aq. HCl andthe product extracted into EtOAc. The EtOAc extract was dried overNa₂SO₄, filtered, and concentrated to give the title intermediate as awhite solid (150 mg).

C₁₂H₁₃N₁O₃ (MW 219.24) mass spectroscopy (MH⁺) 220.2, (MH⁻) 218.4; Anal.Calcd. for C₁₂H₁₃N₁O₃: C, 65.75; H, 5.94; N, 6.39. Found: C, 66.22; H,6.01; N, 6.03.

Step C—Preparation of3-(S)-[2-((1H)-Isoquinoline-3,4-dihydro-3-oxo)-2-methyl-acetyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

To the intermediate from step B (112 mg, 0.511 mmol) in THF (5 mL) wasadded3-(S)-(amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(136 mg, 0.511 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride (98 mg, 0.511 mmol), 1-hydroxybenzotriazole hydrate (70mg, 0.511 mmol), and N,N-diisopropylethylamine (88 μL, 0.511 mmol). Theresulting mixture was stirred overnight at ambient temperature, thendiluted into EtOAc (100 mL) and washed with 10% aqueous citric acid(1×50 mL), brine (1×50 mL), and 1M aqueous K₂CO₃ (1×50 mL). The organiclayer was dried over Na₂SO₄, filtered, concentrated, and the residuepurified by HPLC eluting with hexanes/EtOAc (1:1 gradient to 1:3) toprovide the two separated isomers.

Isomer 1 (60 mg): C₂₈H₂₆N₄O₃ (MW 466.54) mass spectroscopy 466.05; Anal.Calcd. for C₂₈H₂₆N₄O₃: C, 72.10; H, 5.58; N, 12.02. Found: C, 71.99; H,5.80; N, 11.73. Optical rotation: [ ]²⁰ _(D)=18.52 (c 0.5, MeOH); m.p.125-126 C.

Isomer 2 (76 mg): C₂₈H₂₆N₄O₃ (MW 466.54) mass spectroscopy 466.02; Anal.Calcd. for C₂₈H₂₆N₄O₃: C, 72.10; H, 5.58; N, 12.02. Found: C, 72.38; H,5.50; N, 11.72. Optical rotation: [ ]²⁰ _(D)=−137.9 (c 0.5, MeOH); m.p.209-210 C.

Example 10-1 Preparation of3-[N′-3,5-Difluorophenyl-acetamido)-L-alaninyl]-3-amino-2,3-dihydrol-methyl-5-phenyl-1H-1,4benzodiazepine

Following general procedure D, using difluorophenylacetamido and3-(L-alaninyl)-3-amino-2,3-dihydrol-methyl-5-phenyl-1H-1,4-benzodiazepine,as described in Example 8-B above, the title compound was prepared. Themolecular weight as determined by mass spectrometry (FD) was: (M+H).

Example 10-2 Preparation of5-{N′-(N-Acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

Following one or more of the general procedures outlined above, usingacetyl-N-phenylglycine and5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, asdescribed in Example 7-B, the title compound was prepared. The molecularweight as determined by mass spectrometry (FD) was: 485 (M+H).

Additionally, each of the carboxylic acids described above (or thecarboxylic acids prepared by hydrolysis of the above carboxylic acidesters) could be coupled with an appropriate α-amino lactam to providefor compounds of the formulas:

where R¹—(NR⁵)₂)₁—C(X)—NR⁵—Y, R¹—Z—NR⁵—Y, —R₁—SO₂—NR⁵—Y,R₁—Z—NR⁵—NR⁵—C(O)—NR⁵—Y and

are the residues of the associated carboxylic acids (i.e., R¹, R², R⁵,X, X′, X″, Z, l and n are defined above), Y=—CHR²—C(O)—, and W″ isselected from the following structures:

Example Bio-1 Cellular Screen for the Detection of Inhibitors ofβ-amyloid Production

Numerous compounds described above were assayed for their ability toinhibit β-amyloid production in a cell line possessing the Swedishmutation. This screening assay employed cells (K293=human kidney cellline) which were stably transfected with the gene for amyloid precursorprotein 751 (APP751) containing the double mutation LYS₆₅₁, Met₆₅₂ toAsn₆₅₁, LeU₆₅₂ (APP751 numbering) in the manner described inInternational Patent Application Publication No. 94/10569⁸ and Citron etal.¹². This mutation is commonly called the Swedish mutation and thecells, designated as “293 751 SWE”, were plated in Corning 96-wellplates at 2-4×10⁴ cells per well in Dulbecco's minimal essential media(Sigma, St. Louis, Mo.) plus 10% fetal bovine serum. Cell number isimportant in order to achieve β-amyloid ELISA results within the linearrange of the assay (around 0.2 to 2.5 ng per mL).

Following overnight incubation at 37° C. in an incubator equilibratedwith 10% carbon dioxide, media were removed and replaced with 200microliters of a compound described above (drug) containing media perwell for a two hour pretreatment period and cells were incubated asabove. Drug stocks were prepared in 100% dimethyl sulfoxide such that atthe final drug concentration used in the treatment, the concentration ofdimethyl sulfoxide did not exceed 0.5% and, in fact, usually equaled0.1% .

At the end of the pretreatment period, the media were again removed andreplaced with fresh drug-containing media as above and cells wereincubated for an additional two hours. After treatment, plates werecentrifuged in a Beckman GPR at 1200 rpm for five minutes at roomtemperature to pellet cellular debris from the conditioned media. Fromeach well, 100 αL of conditioned media or appropriate dilutions thereofwere transferred into an ELISA plate pre-coated with antibody 266 [P.Seubert, Nature (1992) 359:325-327] against amino acids 13-28 ofβ-amyloid peptide as described in International Patent ApplicationPublication No. 94/10569⁸ and stored at 4° C. overnight. An ELISA assayemploying labelled antibody 3D6 [P. Seubert, Nature (1992) 359:325-327]against amino acids 1-5 of β-amyloid peptide was run the next day tomeasure the amount of β-amyloid peptide produced.

Cytotoxic effects of the compounds were measured by a modification ofthe method of Hansen, et al.¹³ To the cells remaining in the tissueculture plate was added 25 microliters of a3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)(Sigma, St. Louis, Mo.) stock solution (5 mg/mL) to a finalconcentration of 1 mg/mL. Cells were incubated at 37° C. for one hour,and cellular activity was stopped by the addition of an equal volume ofMTT lysis buffer (20% w/v sodium dodecylsulfate in 50%dimethylformamide, pH 4.7). Complete extraction was achieved byovernight shaking at room temperature. The difference in the OD_(562nm)and the OD_(650nm) was measured in a Molecular Device's UV_(max)microplate reader as an indicator of the cellular viability.

The results of the β-amyloid peptide ELISA were fit to a standard curveand expressed as ng/mL β-amyloid peptide. In order to normalize forcytotoxicity, these results were divided by the MTT results andexpressed as a percentage of the results from a drug free control. Allresults are the mean and standard deviation of at least six replicateassays.

The test compounds were assayed for β-amyloid peptide productioninhibition activity in cells using this assay. The results of this assaydemonstrate that the compounds described herein inhibit β-amyloidpeptide production by at least 30% as compared to control.

Example Bio-2 In Vivo Suppression of β-amyloid Release and/or Synthesis

This example illustrates how the compounds of this invention could betested for in vivo suppression of β-amyloid release and/or synthesis.For these experiments, 3 to 4 month old PDAPP mice are used [Games etal., (1995) Nature 373:523-527]. Depending upon which compound is beingtested, the compound is usually formulated at between I and 10 mg/mL.Because of the low solubility factors of the compounds, they may beformulated with various vehicles, such as corn oil (Safeway, South SanFrancisco, Calif.); 10% ethanol in corn oil;2-hydroxypropyl-β-cyclodextrin (Research Biochemicals International,Natick Mass.); and carboxy-ethyl-cellulose (Sigma Chemical Co., St.Louis Mo.).

The mice are dosed subcutaneously with a 26 gauge needle and 3) hourslater the animals are euthanized via CO₂, narcosis and blood is taken bycardiac puncture using a 1 cc 25G 5/8″ tuberculin syringe/needle coatedwith solution of 0.5 M EDTA, pH 8.0. The blood is placed in aBecton-Dickinson vacutainer tube containing EDTA and spun down for 15minutes at 1500×g at 5° C. The brains of the mice are then removed andthe cortex and hippocampus are dissected out and placed on ice.

1. Brain Assay

To prepare hippocampal and cortical tissue for enzyme-linkedimmunosorbent assays (ELISAs) each brain region is homogenized in 10volumes of ice cold guanidine buffer (5.0 M guanidine-HCl, 50 mMTris-HCl, pH 8.0) using a Kontes motorized pestle (Fisher, PittsburghPa.). The homogenates are gently rocked on a rotating platform for threeto four hours at room temperature and stored at −20° C. prior toquantitation of β-amyloid peptide.

The brain homogenates are diluted 1:10 with ice-cold casein buffer[0.25% casein, phosphate buffered saline (PBS), 0.05% sodium azide, 20micrograms/ml aprotinin, 5 mM EDTA, pH 8.0, 10 micrograms/ml leupeptin],thereby reducing the final concentration of guanidine to 0.5 M, beforecentrifugation at 16,000×g for 20 minutes at 4° C. Samples are furtherdiluted, if necessary, to achieve an optimal range for the ELISAmeasurements by the addition of casein buffer with 0.5 M guanidinehydrochloride added. The β-amyloid standards (1-40 or 1-42 amino acids)were prepared such that the final composition equaled 0.5 M guanidine inthe presence of 0.1% bovine serum albumin (BSA).

The total β-amyloid sandwich ELISA, quantitating both β-amyloid (aa1-40) and β-amyloid (aa 1-42) includes two monoclonal antibodies (mAb)to β-amyloid. The capture antibody, 266 [P. Seubert, Nature (1992)359:325-327], is specific to amino acids 13-28 of β-amyloid. Theantibody 3D6 [Johnson-Wood et al., PNAS USA (1997) 94:1550-1555], whichis specific to amino acids 1-5 of β-amyloid, is biotinylated and servesas the reporter antibody in the assay. The 3D6 biotinylation procedureemploys the manufacturer's (Pierce, Rockford Ill.) protocol forNHS-biotin labeling of immunoglobulins except that 100 mM sodiumbicarbonate, pH 8.5 buffer is used. The 3D6 antibody does not recognizesecreted amyloid precursor protein (APP) or full-length APP but detectsonly β-amyloid species with an amino terminal aspartic acid. The assayhas a lower limit of sensitivity of about 50 pg/ml (11 pM) and shows nocrossreactivity to the endogenous murine β-amyloid peptide atconcentrations up to 1 ng/ml.

The configuration of the sandwich ELISA quantitating the level ofβ-amyloid (aa 1-42) employs the mAb 21F12 [Johnson-Wood et al., PNAS USA(1997) 94:1550-1555] (which recognizes amino acids 33-42 of β-amyloid)as the capture antibody. Biotinylated 3D6 is also the reporter antibodyin this assay which has a lower limit of sensitivity of around 125 pg/ml(28 pM).

The 266 and 21F12 capture mAbs are coated at 10 micrograms/ml into 96well immunoassay plates (Costar, Cambidge CIA) overnight at roomtemperature. The plates are then aspirated and blocked with 0.25% humanserum albumin in PBS buffer for at least 1 hour at room temperature,then stored desiccated at 4° C. until use. The plates are rehydratedwith wash buffer (Tris-buffered saline, 0.05% Tween 20) prior to use.The samples and standards are added to the plates and incubatedovernight at 4° C. The plates are washed 3 or more times with washbuffer between each step of the assay. The biotinylated 3D6, diluted to0.5 micrograms/ml in casein incubation buffer (0.25% casein, PBS, 0.05%Tween 20, pH 7.4) is incubated in the well for I hour at roomtemperature. Avidin-HRP (Vector, Burlingame Calif.) diluted 1:4000 incasein incubation buffer is added to the wells for 1 hour at roomtemperature. The colorimetric substrate, Slow TMB-ELISA (Pierce,Cambridge Mass.), is added and allowed to react for 15 minutes, afterwhich the enzymatic reaction is stopped with addition of 2 N H₂SO₄.Reaction product is quantified using a Molecular Devices Vmax (MolecularDevices, Menlo Park Calif.) measuring the difference in absorbance at450 nm and 650 nm.

2. Blood Assay

The EDTA plasma is diluted 1:1 in specimen diluent (0.2 gm/l sodiumphosphate-H₂O (monobasic), 2.16 gm/1 sodium phosphate-7H₂O (dibasic),0.5 gm/l thimerosal, 8.5 gm/l sodium chloride, 0.5 ml Triton X405, 6.0g/l globulin-free bovine serum albumin; and water). The samples andstandards in specimen diluent are assayed using the total β-amyloidassay (266 capture/3D6 reporter) described above for the brain assayexcept the specimen diluent was used instead of the casein diluentsdescribed.

Formulations other than those described above can also be used for oraldelivery and intravenous delivery to a mammal. For oral delivery, thecompound can be mixed with either 100% corn oil or, alternatively, in asolution containing 80% corn oil, 19.5% oleic acid and 0.5% labrafil.The compound can be mixed with the above solutions in concentrationsranging from 1 mg/mL to 10 mg/mL. The compound in solution is preferablyadministered orally to the mammal at a dose volume of 5 mL/kg of bodyweight. For IV delivery, the compound is preferably mixed with asolution of 3% ethanol, 3% solutol HS-15 and 94% saline. The compound ispreferably mixed with the above solution in concentrations ranging from0.25 mg/mL to 5 mg/mL. The compound in solution is preferablyadministered by IV to the mammal at a dose volume of 2 mL/kg of bodyweight.

From the foregoing description, various modifications and changes in thecomposition and method will occur to those skilled in the art. All suchmodifications coming within the scope of the appended claims areintended to be included therein.

What is claimed is:
 1. A method for inhibiting β-amyloid peptide releaseand/or its synthesis in a cell which method comprises administering tosuch a cell an amount of a compound or a mixture of compounds effectivein inhibiting the cellular release and/or synthesis of β-amyloid peptidewherein said compounds are represented by the following formula:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedcycloalkenyl, optionally substituted aryl, optionally substitutedheteroaryl and optionally substituted heterocyclic; Q is S or O; R¹⁵ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, optionally substituted aryl, optionally substituted heterocyclicand optionally substituted heteroaryl; R^(15′) is selected from thegroup consisting of hydrogen, hydroxyl, alkyl, substituted alkyl,optionally substituted aryl, optionally substituted heterocyclic andoptionally substituted heteroaryl; R² is independently selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl and optionallysubstituted heterocyclic; and the moiety:

is selected from the group having the formulas:

 wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene, and —N═CH—;each V is independently selected from the group consisting of hydroxy,acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino,substituted amino, aminoacyl, optionally substituted alkaryl, optionallysubstituted aryl, optionally substituted aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, optionally substituted heteroaryl,thioalkoxy, substituted thioalkoxy, and trihalomethyl; R^(b) is selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, acyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclic; R^(c) is selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclic, cycloalkyl, and substituted cycloalkyl; and tis an integer from 0 to 4; and the pharmaceutically salts thereof; withthe following provisos: when R¹ is trans-cinnamyl, R² is methyl, and R¹⁵is hydrogen, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-onewhen R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ is hydrogen, then W,together with >CH and >C═O, does not form a2,3dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-oneand when R¹—N(R^(15′))C(Q) is (2,5-dimethoxyphenyl)aminocarbonyl and R²is methyl, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.
 2. A methodfor treating a human patient with AD in order to inhibit furtherdeterioration in the condition of that patient which method comprisesadministering to said patient a pharmaceutical composition comprising apharmaceutically inert carrier and an effective amount of a compound ora mixture of compounds of the following formula:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedcycloalkenyl, optionally substituted aryl, optionally substitutedheteroaryl and optionally substituted heterocyclic; Q is S or O; R¹⁵ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, optionally substituted aryl, optionally substituted heterocyclicand optionally substituted heteroaryl, R^(15′) is selected from thegroup consisting of hydrogen, hydroxyl, alkyl, substituted alkyl,optionally substituted aryl, optionally substituted heterocyclic andoptionally substituted lactam and wherein said optionally substitutedlactam heteroaryl, R² is independently selected from the groupconsisting of alkyl substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl,m optionally substituted aryl,optionally substituted heteroaryl and optionally substitutedheterocyclic; and the moiety:

is selected from the group having the formulas:

 wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene, and —N═CH—;each V is independently selected from the group consisting of hydroxy,acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino,substituted amino, aminoacyl, optionally substituted alkaryl, optionallysubstituted aryl, optionally substituted aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, optionally substituted heteroaryl,thioalkoxy, substituted thioalkoxy, and trihalomethyl; R^(b) is selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, acyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclic; R^(c) is selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclic, cycloalkyl, and substituted cycloalkyl; and tis an integer from 0 to 4; and the pharmaceutically salts thereof; withthe following provisos: when R¹ is trans-cinnamyl, R² is methyl, and R¹⁵is hydrogen, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-onewhen R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ is hydrogen, then W,together with >CH and >C═O, does not form a2,3dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-oneand when R¹—N(R^(15′))C(Q) is (2,5-dimethoxyphenyl)aminocarbonyl and R²is methyl, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.
 3. A methodaccording to claims 1 or 2 wherein R¹ is aryl or optionally substitutedheteroaryl.
 4. A method according to claim 3 wherein R¹ is selected fromthe group consisting of (a) alkyl (b) phenyl, (c) a substituted phenylgroup of the formula:

 wherein R^(c) is selected from the group consisting of acyl, alkyl,alkoxy, alkylalkoxy, azido, substituted amino, cyano, halo, hydrogen,nitro, trihalomethyl, thioalkoxy,  and wherein R^(b) and R^(c) are fusedto form a heteroaryl or heterocyclic ring with the phenyl ring whereinthe heteroaryl or heterocyclic ring contains from 3 to 8 atoms of whichfrom 1 to 3 are heteroatoms independently selected from the groupconsisting of oxygen, nitrogen and sulfur R^(b) and R^(b) areindependently selected from the group consisting of hydrogen, halo,nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the provisothat when R^(c) is hydrogen, then R^(b) and R^(b) are either bothhydrogen or both substituents other than hydrogen, (d) 2-naphthyl, (e)2-naphthyl substituted at the 4,5,6,7 and/or 8 positions with 1 to 5substituents selected from the group consisting alkyl, alkoxy, halo,cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl, (f)heteroaryl, and (g) substituted heteroaryl containing 1 to 3substituents selected from the group consisting of alkyl, alkoxy, aryl,aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxyprovided that said substituents are not ortho to the heteroarylattachment to the —NH group.
 5. The method according to claim 3 whereinR¹ is selected from the group consisting of mono-, di- andtri-substituted phenyl groups.
 6. The method according to claim 5wherein R¹ is a disubstituted phenyl selected from the group consistingof 3,5-dichlorophenyl, 3,5-difluorophenyl,3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl,3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.
 7. The methodaccording to claim 5 wherein R¹ is a monosubstituted phenyl selectedfrom the group consisting of 4-azidophenyl, 4-bromophenyl,4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl,4-iodophenyl, 4-(phenylcarbonyl)phenyl, and 4-(1-ethoxy)ethylphenyl. 8.The method according to claim 5 wherein R¹ is a trisubstituted phenylselected from the group consisting of 3,4,5-trifluorophenyl and3,4,5-trichlorophenyl.
 9. The method according to claim 3 wherein R¹ isselected from the group consisting of 2-naphthyl, quinolin-3-yl,2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, and phenyl.
 10. Amethod according to claims 1 or 2 wherein R¹ is selected from the groupconsisting of phenyl, 1-naphthyl, 2-naphthyl, 2-chlorophenyl,2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl,2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl,2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl,4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl,3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl,3-bromophenyl, 3-phenyoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl,3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl,3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di(trifluoromethyl)phenyl,3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,3,4,5-tri(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,2,4,6-trimethylphenyl, 2,4,6-tri(trifluoromethyl)phenyl,2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl,3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl,iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl,n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, —CH₂-cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl, pyrid-2-yl,pyrid-3-ly, pyrid-4-yl, fluoropyridyls, chloropryidyls, thien-2-yl,thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl,benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl,thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl,3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl,1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl,(CH₃)₂CH═CHCH₂CH₂CH(CH₃)—, C(O)CH₂—, thien-2-yl-methyl,2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl,2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl,(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,(3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl,(4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl,(4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl,(4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl,(1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl,(4-methoxyphenyl)ethyl, CH₃OC(O)CH₂—, benzylthiomethyl,5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl,(2-methylbenzofuran-3-yl), methoxymethyl, CH₃CH═CH—, CH₃CH₂CH═CH—,(4-chlorophenyl)C(O)CH₂—, (4-fluorophenyl)C(O)CH₂—,(4-methoxyphenyl)C(O)CH₂—, 4-(fluorophenyl)-NHC(O)CH₂—,1-phenyl-n-butyl, (phenyl)₂CHNHC(O)CH₂CH₂—, (CH₃)₂NC(O)CH₂—,(phenyl)₂CHNHC(O)CH₂CH₂—, methylcarbonylmethyl,(2,4-dimethylphenyl)C(O)CH₂—, 4-methoxyphenyl-C(O)CH₂—, phenyl-C(O)CH₂—,CH₃C(O)N(phenyl)—, ethenyl, methylthiomethyl, (CH₃)₃CNHC(O)CH₂—,4-fluorophenyl-C(O)CH₂—, diphenylmethyl, phenoxymethyl,3,4-methylenedioxyphenyl-CH₂—, benzo[b]thiophen-3-yl,(CH₃)₃COC(O)NHCH₂—, trans-styryl, H₂NC(O)CH₂CH₂—,2-trifluoromethylphenyl-C(O)CH₂, C(O)NHCH(phenyl)CH₂—, mesityl,CH₃CH(═NHOH)CH₂—, 4-CH₃-phenyl-NHC(O)CH₂CH₂—, C(O)CH(phenyl)CH₂—,(CH₃)₂CHC(O)NHCH(phenyl)—, CH₃CH₂OCH₂—, CH₃OC(O)CH(CH₃)(CH₂)₃—,2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH₃-benzofuran-3-yl,2-(2,4-dichlorophenoxy)ethyl, SO₂CH₂—, 3-cyclohexyl-n-propyl,CF₃CH₂CH₂CH₂— and N-pyrrolidinyl.
 11. A method according to claims 1 or2 where each R² is independently selected from the group consisting ofalkyl, substituted alkyl, alkenyl, cycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl and optionally substitutedheterocyclic.
 12. The method according to claim 11 wherein R² isselected from the group consisting of methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH₂CH(CH₂CH₃)₂,2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl,cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl,—CH₂-cyclopropyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclohexyl, —CH₂-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,p-(N-morpholino-CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thiophen-2-yl,—CH₂(1-methyl)cyclopropyl, —CH₂-thiophen-3-yl, thiophen-3-yl,thiophen-2-yl, —CH₂-C(O)O-t-butyl, —CH₂-C(CH₃)₃, —CH₂CH(CH₂CH₃)₂,2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH₃)₂]COOCH₃,—CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂, —CH₂CH═CHCH₃ (cis and trans), —CH₂OH,—CH(OH)CH₃, —CH(O-t-butyl)CH₃, —CH₂OCH₃, —(CH₂)₄NH-Boc, —(CH₂)₄NH₂,—CH₂-pyridyl, pyridyl, —CH₂-naphthyl, —CH₂—(N-morpholino),p-(N-morpholino-CH₂CH₂O)-benzyl, benzo[b]thiophen-2-yl,5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl,benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, —CH₂CH₂SCH₃, thien-2-yl,and thien-3-yl.
 13. The method of claims 1 or 2 wherein the—C(H)_(p)WC(O) moiety is selected from the group having the formulas:

wherein R^(b), R^(c), V and t are as defined in claims 1 or 2,respectively.
 14. A pharmaceutical composition comprising apharmaceutically inert carrier and a pharmaceutically effective amountof a compound of formula IA:

wherein R¹ is selected from the group consisting of: A) alkyl of from 1to 20 carbon atoms; B) alkenyl of from 2 to 10 carbon atoms and 1-2sites of alkenyl unsaturation; C) alkynyl of from 2 to 10 carbon atomsand from 1-2 sites of alkynyl unsaturation; D) cycloalkyl of from 3 to12 carbon atoms; E) cycloalkenyl of from 4 to 12 carbon atoms; F)substituted alkyl of from 1 to 10 carbon atoms, having from 1 to 3substituents selected from: 1) alkoxy having the formula alkyl-O—wherein alkyl is as defined in A herein; 2) substituted alkoxy of theformula substituted alkyl-O— wherein substituted alkyl is as defined inF herein; 3) cycloalkyl as defined in D herein; 4) substitutedcycloalkyl as defined in I herein; 5) cycloalkenyl as defined in Eherein; 6) substituted cycloalkenyl as defined in J herein; 7) acylhaving a formula selected from the group consisting of alkyl-C(O)—,substituted alkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,optionally substituted aryl-C(O)—, optionally substitutedheteroaryl-C(O)— and optionally substituted heterocyclic-C(O)— whereinalkyl is defined in A herein; wherein substituted alkyl is defined in Fherein; wherein cycloalkyl is defined in D herein; wherein substitutedcycloalkyl is defined in I herein; wherein optionally substituted arylis defined in F25 herein; wherein optionally substituted heteroaryl isdefined in F27 herein; and wherein optionally substituted heterocyclicis defined in F29 herein; 8) acylamino having the formula —C(O)NRRwherein each R is independently hydrogen, alkyl, substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted heterocyclic wherein alkyl is defined in Aherein; wherein substituted alkyl is defined in F herein; whereinoptionally substituted aryl is defined in F25 herein; wherein optionallysubstituted heteroaryl is defined in F27 herein; and wherein optionallysubstituted heterocyclic is defined in F29 herein; 9) acyloxy having aformula selected from the group consisting of alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, optionally substituted aryl-C(O)O—,optionally substituted heteraryl-C(O)O— and optionally substitutedheterocyclic-C(O)O— wherein alkyl is defined in A herein; whereinsubstituted alkyl is defined in F herein; wherein cycloalkyl is definedin D herein; wherein optionally substituted aryl is defined in F25herein; wherein optionally substituted heteroaryl is defined in F27herein; and wherein optionally substituted heterocyclic is defined inF29 herein; 10) amino; 11) substituted amino having the formula —N(R)₂wherein each R is independently selected from the group consisting of:a) hydrogen; b) alkyl as defined in A herein; c) substituted alkyl asdefined in F herein; d) alkenyl as defined in B herein; e) substitutedalkenyl as defined in G herein; f) alkynyl as defined in C herein; g)substituted alkynyl as defined in H herein; h) optionally substitutedaryl as defined in F25 herein; i) cycloalkyl as defined in D herein; j)substituted cycloalkyl as defined in I herein; k) optionally substitutedheteroaryl as defined in F27 herein; and l) optionally substitutedheterocyclic as defined in F29 herein;  wherein both R groups may bejoined together to form a heterocyclic group as defined in F29 herein;and 12) aminoacyl having the formula —NRC(O)R wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein heteroaryl is defined in F27 herein; andwherein optionally substituted heterocyclic is defined in F29 herein;13) aminoacyloxy having the formula —NRC(O)OR wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein optionally substituted heteroaryl isdefined in F27 herein; and wherein optionally substituted heterocyclicis defined in F29 herein; 14) oxyacylamino having the formula —OC(O)NRRwherein each R is independently hydrogen, alkyl, substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl, 15) oroptionally substituted heterocyclic wherein alkyl is defined in Aherein; wherein substituted alkyl is defined in F herein; whereinoptionally substituted aryl is defined in F25 herein; wherein optionallysubstituted heteroaryl is defined in F27 herein; and wherein optionallysubstituted heterocyclic is defined in F29 herein; 15) cyano; 16)halogen selected from fluoro, chloro, bromo and iodo; 17) hydroxyl; 18)keto; 19) thioketo; 20) carboxyl; 21) optionally substitutedcarboxyalkyl having the formula —C(O)O-alkyl and —C(O)O-substitutedalkyl wherein alkyl is as defined in A and substituted alkyl is asdefined in F; 22) thiol; 23) thioalkoxy having the formula —S-alkyl,wherein alkyl is defined in A herein; 24) substituted thioalkoxy havingthe formula —S-substituted alkyl, wherein substituted alkyl is definedin F herein; 25) optionally substituted aryl having 6 to 14 carbon atomsand optionally substituted with 1 to 5 substituents selected from: a)acyloxy; b) hydroxy; c) acyl as defined in F7 herein; d) alkyl asdefined in A herein; e) alkoxy as defined in F1 herein; f) alkenyl asdefined in B herein; g) alkynyl as defined in C herein; h) substitutedalkyl as defined in F herein; i) substituted alkoxy as defined in F2herein; j) substituted alkenyl as defined in G herein; k) substitutedalkynyl as defined in H herein; l) amino; m) substituted amino asdefined in F11 herein; n) aminoacyl as defined in F12 herein; o)acylamino as defined in F8 herein; p) optionally substituted alkaryl ofthe formula -alkylene-aryl where alkylene has from 1 to 10 carbon atomsand is optionally substituted with from 1 to 3 substituents selectedfrom the group consisting of: 1) alkoxy as defined in F1 herein; 2)substituted alkoxy as defined in F2 herein; 3) acyl as defined in F7herein; 4) acylamino as defined in F8 herein; 5) acyloxy as defined inF9 herein; 6) amino; 7) substituted amino as defined in F11 herein; 8)aminoacyl as defined in F12 herein; 9) aminoacyloxy as defined in F13herein; 10) oxyacylamino as defined in F14 herein; 11) cyano; 12)halogen selected from fluoro, chloro, bromo and iodo; 13) hydroxyl; 14)keto; 15) thioketo; 16) carboxyl; 17) optionally substitutedcarboxyalkyl as defined in F21; 18) thiol; 19) thioalkoxy as defined inF23 herein; 20) substituted thioalkoxy as defined in F24 herein; 21)optionally substituted aryl as defined in F25 herein; 22) optionallysubstituted heteroaryl as defined in F27 herein; 23) optionallysubstituted saturated or unsaturated heterocyclic as defined in F29herein; 24) heterocyclooxy as defined in G24 herein; 25) nitro; 26)mono- and di-alkylamino as defined in F41 herein; 27) mono- anddi-(substituted alkyl) amino as defined in F42 herein; 28) mono- anddi-arylamino as defined in F43 herein; 29) mono- and di-heteroarylaminoas defined in F44 herein; 30) mono- and di-heterocyclic amino as definedin F45 herein; and 31) unsymmetric di-substituted amines as defined inF46 herein; q) optionally substituted aryl as defined in F25 herein; r)optionally substituted aryloxy as defined in F26 herein; s) azido; t)carboxyl; u) optionally substituted carboxylalkyl as defined in F21herein; v) cyano; w) halo as defined in F16 herein; x) nitro; y)optionally substituted heteroaryl as defined in F27 herein; z)optionally substituted heteroaryloxy as defined in F28 herein aa)optionally substituted heterocyclic as defined in F29 herein; bb)optionally substituted heterocyclooxy as defined in G24 herein; cc)aminoacyloxy as defined in F13 herein; dd) oxyacylamino as defined inF14 herein; ee) thioalkoxy as defined in F23 herein; ff) substitutedthioalkoxy as defined in F24 herein; gg) optionally substitutedthioaryloxy having the formula aryl-S— wherein aryl is optionallysubstituted as defined in F25 herein; hh) optionally substitutedthioheteroaryloxy having the formula heteroaryl-S— wherein heteroaryl isoptionally substituted as defined in F27 herein; ii) —SO-alkyl whereinalkyl is as defined in A herein; jj) —SO-substituted alkyl whereinsubstituted alkyl is as defined in F herein; kk) —SO-optionallysubstituted aryl wherein optionally substituted aryl is as defined inF25 herein; ll) —SO-optionally substituted heteroaryl wherein optionallysubstituted heteroaryl is as defined in F27 herein; mm) —SO₂-alkylwherein alkyl is as defined in A herein; nn) —SO₂-substituted alkylwherein substituted alkyl is as defined in F herein; oo) —SO₂-optionallysubstituted aryl wherein optionally substituted aryl is as defined inF25 herein; pp) —SO₂-optionally substituted heteroaryl whereinoptionally substituted heteroaryl is as defined in F27 herein; and qq)trihalomethyl wherein halo is as defined in F16 herein; 26) optionallysubstituted aryloxy having the formula aryl-O— wherein aryl isoptionally substituted aryl as defined in F25 herein; 27) optionallysubstituted heteroaryl having 1 to 15 ring carbon atoms and 1 to 4 ringheteroatoms selected from oxygen, nitrogen and sulfur and optionallysubstituted with 1 to 5 substituents selected from the group ofsubstituents as defined in F25 herein 28) optionally substitutedheteroaryloxy having the formula —O-heteroaryl wherein heteroaryl isoptionally substituted heteroaryl as defined in F27 herein; 29)optionally substituted saturated or unsaturated heterocyclic having from1 to 15 ring carbon atoms and from 1 to 4 ring heteroatoms selected fromnitrogen, sulfur and oxygen and optionally substituted with 1 to 5substituents selected from the group of substituents consisting of alkylas defined in A herein; substituted alkyl as defined in F herein; alkoxyas defined in F1 herein; substituted alkoxy as defined in F2 herein;aryl as defined in F25 herein; aryloxy, halo as defined in F16 herein;nitro, heteroaryl as defined in F27 herein; thiol, thioalkoxy as definedin F23 herein; substituted thioalkoxy as defined in F24 herein;thioaryloxy wherein aryloxy is as defined in F26 herein; andtrihalomethyl wherein halo is as defined in F16 herein; 30)hydroxyamino; 31) alkoxyamino wherein alkoxy is as defined in F1; 32)nitro; 33) —SO-alkyl wherein alkyl is as defined in A herein; 34)—SO-substituted alkyl wherein substituted alkyl is as defined in Fherein; 35) —SO-optionally substituted aryl wherein aryl is optionallysubstituted as defined in F25 herein; 36) —SO-optionally substitutedheteroaryl wherein optionally substituted heteroaryl is as defined inF27 herein; 37) —SO₂-alkyl wherein alkyl is as defined in A herein; 38)—SO₂-substituted alkyl wherein substituted alkyl is as defined in Fherein; 39) —SO₂-optionally substituted aryl wherein optionallysubstituted aryl is as defined in F25 herein; 40) —SO₂-optionallysubstituted heteroaryl wherein optionally substituted heteroaryl is asdefined in F27 herein; 41) mono- and di-alkylamino wherein alkyl is asdefined in A herein; 42) mono- and di-(substituted alkyl) amino whereinsubstituted alkyl is as defined in F herein; 43) mono- and di-arylaminowherein aryl is as defined in F25 herein; 44) mono- anddi-heteroarylamino wherein heteroaryl is as defined in F27 herein; 45)mono- and di-heterocyclic amino wherein heterocyclic is as defined inF29 herein; and 46) unsymmetric di-substituted amines having differentsubstituents selected from alkyl, substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl and optionallysubstituted heterocyclic, wherein alkyl is defined in A herein; whereinsubstituted alkyl is defined in F herein; wherein optionally substitutedaryl is defined in F25 herein; wherein optionally substituted heteroarylis defined in F27 herein; and wherein optionally substitutedheterocyclic is defined in F29 herein; G) substituted alkenyl having 2to 10 carbon atoms and having of from 1 to 3 substituents selected fromthe group consisting of: 1) alkoxy having the formula alkyl-O— whereinalkyl is as defined in A herein; 2) substituted alkoxy of the formulasubstituted alkyl-O— wherein substituted alkyl is as defined in Fherein; 3) acyl as defined in F7 herein; 4) acylamino as defined in F8herein; 5) acyloxy as defined in F9 herein; 6) amino; 7) substitutedamino as defined in F11 herein; 8) aminoacyl as defined in F12 herein;9) aminoacycloxy as defined in F13 herein; 10) oxyacylamino as definedin F14 herein; 11) cyano; 12) halogen selected from fluoro, cholo, bromoand iodo; 13) hydroxyl; 14) keto; 15) thioketo; 16) carboxyl; 17)optionally substituted carboxyalkyl having the formula —C(O)O-alkyl and—C(O)O-substituted alkyl wherein alkyl is as defined in A andsubstituted alkyl is as defined in F; 18) thiol; 19) thioalkoxy asdefined in F23 herein; 20) substituted thioalkoxy as defined in F24herein; 21) optionally substituted aryl as defined in F25 herein; 22)optionally substituted heteroaryl as defined in F27 herein; 23)optionally substituted saturated or unsaturated heterocyclic as definedin F29 herein; 24) optionally substituted heterocyclooxy having theformula —O-heterocyclic wherein heterocyclic is as defined in F29herein; 25) nitro; 26) —SO-alkyl wherein alkyl is as defined in Aherein; 27) —SO-substituted alkyl wherein substituted alkyl is asdefined in F herein; 28) —SO-aryl wherein optionally substituted aryl isoptionally substituted as defined in F25 herein; 29) —SO-optionallysubstituted heteroaryl wherein optionally substituted heteroaryl is asdefined in F27 herein; 30) —SO₂-alkyl wherein alkyl is as defined in Aherein; 31) —SO₂-substituted alkyl wherein substituted alkyl is asdefined in F herein; 32) —SO₂-optionally substituted aryl whereinoptionally substituted aryl is as defined in F25 herein; and 33)—SO₂-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; 34) mono- and di-alkylamino asdefined in F41 herein; 35) mono- and di-(substituted alkyl) amino asdefined in F42 herein; 36) mono- and di-arylamino as defined in F43herein; 37) mono- and di-heteroarylamino as defined in F44 herein; 38)mono- and di-heterocyclic amino as defined in F29 herein; and 39)unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl and optionally substituted heterocyclic; H)substituted alkynyl having 2 to 10 carbon atoms having 1-2 sites ofalkynyl unsaturation and having 1 to 3 substituents selected from thegroup consisting of: 1) alkoxy as defined in F1 herein; 2) substitutedalkoxy as defined in F2 herein; 3) acyl as defined in F7 herein; 4)acylamino as defined in F8 herein; 5) acyloxy as defined in F9 herein;6) amino; 7) substituted amino as defined in F11 herein; 8) aminoacyl asdefined in F12 herein; 9) aminoacyloxy as defined in F13 herein; 10)oxyacylamino as defined in F14 herein, 11) cyano; 12) halogen as definedin F16 herein; 13) hydroxyl; 14) keto; 15) thioketo; 16) carboxyl; 17)carboxylalkyl as defined in F21 herein; 18) thiol; 19) thioalkoxy asdefined in F23 herein; 20) substituted thioalkoxy as defined in F24herein; 21) aryl as defined in F25 herein; 22) heteroaryl as defined inF27 herein; 23) heterocyclic as defined in F29 herein; 24)heterocyclooxy as defined in G24 herein; 25) nitro; 26) —SO-alkyl asdefined in F33 herein; 27) —SO-substituted alkyl as defined in F34herein; 28) —SO-aryl as defined in F35 herein; 29) —SO-heteroaryl asdefined in F36 herein; 30) —SO₂-alkyl as defined in F37 herein; 31)—SO₂-substituted alkyl as defined in F38 herein; 32) —SO₂-aryl asdefined in F39 herein; 33) —SO₂-heteroaryl as defined in F40 herein; 34)mono- and di-alkylamino as defined in F41 herein; 35) mono- anddi-(substituted alkyl) amino as defined in F42 herein; 36) mono- anddi-arylamino as defined in F43 herein; 37) mono- and di-heteroarylaminoas defined in F44 herein; 38) mono- and di-heterocyclic amino as definedin F42 herein; and 39) unsymmetric di-substituted amines as defined inF29 herein; I) substituted cycloalkyl having 3 to 12 carbon atoms andhaving from 1 to 5 substituents selected from the group of substituentsconsisting of: 1) hydroxy; 2) acyl as defined in F7 herein; 3) acyloxyas defined in F9 herein; 4) alkyl as defined in A herein; 5) substitutedalkyl as defined in F herein; 6) alkoxy as defined in F1 herein; 7)substituted alkoxy as defined in F2 herein; 8) alkenyl as defined in Bherein; 9) substituted alkenyl as defined in G herein; 10) alkynyl asdefined in C herein; 11) substituted alkynyl as defined in H herein, 12)amino; 13) substituted amino as defined in F11 herein; 14) aminoacyl asdefined in F12 herein; 15) alkaryl as defined in F25(p) herein; 16) arylas defined in F29 herein; 17) aryloxy as defined in F26 herein; 18)carboxyl; 19) carboxylalkyl as defined in F21 herein; 20) cyano; 21)halo as defined in F16 herein; 22) nitro; 23) heteroaryl as defined inF27 herein; 24) thioalkoxy as defined in F23 herein; 25) substitutedthioalkoxy as defined in F24 herein; and 26) trihalomethyl; J)substituted cycloalkenyl as defined in E herein having from 1 to 5substituents selected from the group of consisting of: 1) hydroxy; 2)acyl as defined in F7 herein; 3) acyloxy as defined in F9 herein; 4)alkyl as defined in A herein; 5) substituted alkyl as defined in Fherein; 6) alkoxy as defined in F1 herein; 7) substituted alkoxy asdefined in F2 herein; 8) alkenyl as defined in B herein; 9) substitutedalkenyl as defined in G herein; 10) alkynyl as defined in C herein; 11)substituted alkynyl as defined in H herein; 12) amino; 13) substitutedamino as defined in F11 herein; 14) aminoacyl as defined in F12 herein;15) alkaryl as defined in F25(p) herein; 16) aryl as defined in F29herein; 17) aryloxy as defined in F26 herein; 18) carboxyl; 19)carboxylalkyl as defined in F21 herein; 20) cyano; 21) halo as definedin F16 herein; 22) nitro; 23) heteroaryl as defined in F27 herein; 24)thioalkoxy as defined in F23 herein; 25) substituted thioalkoxy asdefined in F24 herein; and 26) trihalomethyl; K) optionally substitutedaryl as defined in F25 herein; L) optionally substituted heteroaryl asdefined in F27 herein; and M) optionally substituted heterocyclic asdefined in F29 herein; R² is independently selected from the groupconsisting of: O) alkyl as defined in A herein; P) substituted alkyl asdefined in F herein; Q) alkenyl of from 2 to 10 carbon atoms and 1-2sites of alkenyl unsaturation; R) substituted alkenyl as defined in Gherein; S) alkynyl of from 2 to 10 carbon atoms and from 1-2 sites ofalkynyl unsaturation; T) substituted alkynyl as defined in H herein; U)cycloalkyl of from 3 to 12 carbon atoms; V) optionally substituted arylas defined in F25 herein; W) optionally substituted heteroaryl asdefined in F27 herein; and X) optionally substituted heterocyclic asdefined in F29 herein; Q is S and O;  wherein R¹⁵ is independentlyselected from the group consisting of: Y) hydrogen; Z) alkyl as definedin A herein; AA) substituted alkyl as defined in F herein; AB)optionally substituted aryl as defined in F25 herein; AC) optionallysubstituted heterocyclic as defined in F29 herein; AD) optionallysubstituted heteroaryl as defined in F27 herein;  wherein R^(15′) isindependently selected from the group consisting of: AE) hydrogen; AF)hydroxyl; AG) alkyl as defined in A herein; AH) substituted alkyl asdefined in F herein; AI) optionally substituted aryl as defined in F25herein; AJ) optionally substituted heterocyclic as defined in F29herein; AK) optionally substituted heteroaryl as defined in F27 herein;and the moiety:

 is selected from the group having the formulas:

 wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene, and —N═CH—;each V is independently selected from the group consisting of hydroxy,acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino,substituted amino, aminoacyl, optionally substituted alkaryl, optionallysubstituted aryl, optionally substituted aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, optionally substituted heteroaryl,thioalkoxy, substituted thioalkoxy, and trihalomethyl; R^(b) is selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocyclic; R^(c) is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclic, thioalkoxy, substituted amino,cycloalkyl, and substituted cycloalkyl; and t is an integer from 0 to 4;or pharmaceutically salts thereof; with the following provisos: when R¹is trans-cinnamyl, R² is methyl, and R¹⁵ is hydrogen, then W, togetherwith >CH and >C═O, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-onewhen R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ is hydrogen, then W,together with >CH and >C═O, does not form a2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-onewhen R¹-N(R^(15′))C(Q) is (2,5-dimethoxyphenyl)aminocarbonyl and R² ismethyl, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one and  when Q isS, R¹⁵ and R^(15′) are hydrogen, and the moiety:

 is selected from the group having the formulas:

 then R¹ is not phenyl.
 15. The pharmaceutical composition according toclaim 4, wherein the moiety:

each V is independently selected from the group consisting of hydroxy,acyl as defined in F7, acyloxy as defined in F9, alkyl as defined in A,substituted alkyl as defined in F, alkoxy as defined in F1, substitutedalkoxy as defined in F2, alkenyl as defined in B, substituted alkenyl asdefined in G, alkynyl as defined in C, substituted alkynyl as defined inH, amino, substituted amino as defined in F11, aminoacyl as defined inF12, optionally substituted alkaryl as defined in F25, optionallysubstituted aryl as defined in F25, optionally substituted aryloxy asdefined in F26, carboxyl, carboxyalkyl, cyano, halo, nitro, optionallysubstituted heteroaryl as defined in F27, thioalkoxy, substitutedthioalkoxy as defined in F24, and trihalomethyl; and t is an integerfrom 0 to 4; R^(b) is selected from the group consisting of alkyl,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, alkynyl, acyl, optionally substituted aryl as defined inF25, optionally substituted heteroaryl as defined in F27, and optionallysubstituted heterocyclic as defined in F29; or pharmaceuticallyacceptable salts thereof.
 16. The pharmaceutical composition accordingto claim 14, wherein the moiety:

wherein R^(b) is selected from the group consisting of alkyl,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, alkynyl, acyl, optionally substituted aryl as defined inF25, optionally substituted heteroaryl as defined in F27, and optionallysubstituted heterocyclic as defined in F29; R^(c) is selected from thegroup consisting of alkyl as defined in A, substituted alkyl as definedin F, alkenyl, substituted alkenyl as defined in G, optionallysubstituted aryl as defined in F25, optionally substituted heteroaryl asdefined in F27, optionally substituted heterocyclic as defined in F29,cycloalkyl, and substituted cycloalkyl as defined in I; each V isindependently selected from the group consisting of hydroxy, acyl asdefined in F7, acyloxy as defined in F9, alkyl as defined in A,substituted alkyl as defined in F, alkoxy as defined in F1, substitutedalkoxy as defined in F2, alkenyl as defined in B, substituted alkenyl asdefined in G, alkynyl as defined in C, substituted alkynyl as defined inH, amino, substituted amino as defined in F11, aminoacyl as defined inF12, optionally substituted alkaryl as defined in F25, optionallysubstituted aryl as defined in F25, optionally substituted aryloxy asdefined in F26, carboxyl, carboxyalkyl, cyano, halo, nitro, optionallysubstituted heteroaryl as defined in F27, thioalkoxy, substitutedthioalkoxy as defined in F24, and trihalomethyl; and t is an integerfrom 0 to 4; or pharmaceutically acceptable salts thereof.
 17. Thepharmaceutical composition according to claim 14, wherein the moiety:

wherein R^(b) is selected from the group consisting of alkyl,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, alkynyl, acyl, optionally substituted aryl as defined inF25, optionally substituted heteroaryl as defined in F27, and optionallysubstituted heterocyclic as defined in F29; R^(c) is selected from thegroup consisting of alkyl as defined in A, substituted alkyl as definedin F, alkenyl, substituted alkenyl as defined in G, optionallysubstituted aryl as defined in F25, optionally substituted heteroaryl asdefined in F27, optionally substituted heterocyclic as defined in F29,cycloalkyl, and substituted cycloalkyl as defined in I; each V isindependently selected from the group consisting of hydroxy, acyl asdefined in F7, acyloxy as defined in F9, alkyl as defined in A,substituted alkyl as defined in F, alkoxy as defined in F1, substitutedalkoxy as defined in F2, alkenyl as defined in B, substituted alkenyl asdefined in G, alkynyl as defined in C, substituted alkynyl as defined inH, amino, substituted amino as defined in F11, aminoacyl as defined inF12, optionally substituted alkaryl as defined in F25, optionallysubstituted aryl as defined in F25, optionally substituted aryloxy asdefined in F26, carboxyl, carboxyalkyl, cyano, halo, nitro, optionallysubstituted heteroaryl as defined in F27, thioalkoxy, substitutedthioalkoxy as defined in F24, and trihalomethyl; and t is an integerfrom 0 to 4; w is an integer from 0 to 3; or pharmaceutically acceptablesalts thereof.
 18. The pharmaceutical composition according to claim 14,wherein the moiety:

wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene and —N═CH—;R^(c) is selected from the group consisting of alkyl as defined in A,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, optionally substituted aryl as defined in F25, optionallysubstituted heteroaryl as defined in F27, optionally substitutedheterocyclic as defined in F29, cycloalkyl, and substituted cycloalkylas defined in I; each V is independently selected from the groupconsisting of hydroxy, acyl as defined in F7, acyloxy as defined in F9,alkyl as defined in A, substituted alkyl as defined in F, alkoxy asdefined in F1, substituted alkoxy as defined in F2, alkenyl as definedin B, substituted alkenyl as defined in G, alkynyl as defined in C,substituted alkynyl as defined in H, amino, substituted amino as definedin F11, aminoacyl as defined in F12, optionally substituted alkaryl asdefined in F25, optionally substituted aryl as defined in F25,optionally substituted aryloxy as defined in F26, carboxyl,carboxyalkyl, cyano, halo, nitro, optionally substituted heteroaryl asdefined in F27, thioalkoxy, substituted thioalkoxy as defined in F24,and trihalomethyl; and t is an integer from 0 to 4; w is an integer from0 to 3; or pharmaceutically acceptable salts thereof.
 19. Thepharmaceutical composition according to claim 14, wherein the moiety:

R^(c) is selected from the group consisting of alkyl as defined in A,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, optionally substituted aryl as defined in F25, optionallysubstituted heteroaryl as defined in F27, optionally substitutedheterocyclic as defined in F29, cycloalkyl, and substituted cycloalkylas defined in I; each V is independently selected from the groupconsisting of hydroxy, acyl as defined in F7, acyloxy as defined in F9,alkyl as defined in A, substituted alkyl as defined in F, alkoxy asdefined in F1, substituted alkoxy as defined in F2, alkenyl as definedin B, substituted alkenyl as defined in G, alkynyl as defined in C,substituted alkynyl as defined in H, amino, substituted amino as definedin F11, aminoacyl as defined in F12, optionally substituted alkaryl asdefined in F25, optionally substituted aryl as defined in F25,optionally substituted aryloxy as defined in F26, carboxyl,carboxyalkyl, cyano, halo, nitro, optionally substituted heteroaryl asdefined in F27, thioalkoxy, substituted thioalkoxy as defined in F24,and trihalomethyl; and t is an integer from 0 to 4; w is an integer from0 to 3; or pharmaceutically acceptable salts thereof.
 20. Thepharmaceutical composition according to claim 19, wherein R¹ is selectedfrom the group consisting of: (a) alkyl; (b) phenyl; (c) a substitutedphenyl group of the formula:

 wherein R^(c) is selected fron the group consisting of acyl, alkyl,alkoxy, alkylalkoxy, azido, cyano, subsstituted amino, halo, hydrogen,nitro, trihalomethyl, thioalkoxy, and wherein R^(b) and R^(c) are fusedto form a heteroaryl or heterocyclic ring with the phenyl ring whereinthe heteroaryl or heterocyclic ring contains from 3 to 8 atoms of whichfrom 1 to 3 are heteroatoms independently selected from the groupconsisting of oxygen, nitrogen and sulfur, R^(b) and R^(b′) areindependently selected from the group consisting of hydrogen, halo,nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the provisothat when R^(c) is hydrogen, the R^(b) and R^(b′) are either bothhydrogen or both substituents other than hydrogen, (d) 2-naphthyl, (e)2-naphthyl substituted at the 4,5,6,7 and/or 8 positions with 1 to 5substituents selected from the group consisting of alkyl, alkoxy, halo,cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl, (f)heteroaryl, and (g) substituted heteroaryl containing 1 to 3substituents selected from the group consisting of alkyl, alkoxy, aryl,aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxyprovided that said substituents are not othro to the heteroarylattachment to the —NH group.
 21. The pharmaceutical compositionaccording to claim 14, wherein R¹ is selected from the group consistingof mono-, di-, and tri-substituted phenyl groups.
 22. The pharmaceuticalcomposition according to claim 21, wherein R¹ is a monosubstitutedphenyl selected from the group consisting of 4-azidophenyl,4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl,4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)-phenyl, and4-(1-ethoxy)ethylphenyl.
 23. The pharmaceutical composition according toclaim 21, wherein R¹ is a disubstituted phenyl selected from the groupconsisting of 3,5-dichlorophenyl, 3,5-difluorophenyl,3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl,3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.
 24. Thepharmaceutical composition according to claim 21, wherein R¹ is atrisubstituted phenyl selected from the group consisting of3,4,5-trifluorophenyl and 3,4,5-tricholorophenyl.
 25. The pharmaceuticalcomposition according to claim 14, wherein R¹ is selected from the groupconsisting of 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl,benzothiazol-6-yl, 5-indolyl and phenyl.
 26. The pharmaceuticalcomposition according to claim 14, wherein R¹ is selected from the groupconsisting of: phenyl, 1-naphthyl, 2-naphthyl, 2-chlorophenyl,2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl,2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl,2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl,4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl,3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl,3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl,3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl,3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl,3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl,3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl,iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl,n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, —CH₂-cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl, pyrid-2-yl,pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl,thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl,benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl,thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl,3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl,1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl,(CH₃)₂CH═CHCH₂CH₂CH(CH₃)—, C(O)CH₂—, thien-2-yl-methyl,2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl,2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl,(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,(3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl,(4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl,(4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl,(4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl,(1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl,(4-methoxyphenyl)ethyl, CH₃OC(O)CH₂—, benzylthiomethyl,5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl,(2-methylbenzofuran-3-yl), methoxymethyl, CH₃CH═CH—, CH₃CH₂CH═CH—,(4-chlorophenyl)C(O)CH₂—, (4-fluorophenyl)C(O)CH₂—,(4-methoxyphenyl)C(O)CH₂—, 4-(fluorophenyl)—NHC(O)CH₂—,1-phenyl-n-butyl, (phenyl)₂CHNHC(O)CH₂CH₂—, (CH₃)₂NC(O)CH₂—,(phenyl)₂CHNHC(O)CH₂CH₂—, ethylcarbonylmethyl,(2,4-dimethylphenyl)C(O)CH₂—, 4-methoxyphenyl-C(O)CH₂—, phenyl-C(O)CH₂—,CH₃C(O)N(phenyl)—, ethenyl, methylthiomethyl, (CH₃)₃CNHC(O)CH₂—,4-fluorophenyl-C(O)CH₂—, diphenylmethyl, phenoxymethyl,3,4-methylenedioxyphenyl-CH₂—, benzo[b]thiophen-3-yl,(CH₃)₃COC(O)NHCH₂—, trans-styryl, H₂NC(O)CH₂CH₂—,2-trifluoromethylphenyl-C(O)CH₂, phenyl-C(O)NHCH(phenyl)CH₂—, mesityl,CH₃CH(═NHOH)CH₂—, 4-CH₃-phenyl-NHC(O)CH₂CH₂—, C(O)CH(phenyl)CH₂—,(CH₃)₂CHC(O)NHCH(phenyl)—, CH₃CH₂OCH₂—, CH₃OC(O)CH(CH₃)(CH₂)₃—,2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH₃-benzofuran-3-yl,2-(2,4-dichlorophenoxy)ethyl, SO₂CH₂—, 3-cyclohexyl-n-propyl,CF₃CH₂CH₂CH₂— and N-pyrrolidinyl.
 27. The pharmaceutical compositionaccording to claim 14, wherein R² is selected from the group consistingof alkyl, substituted alkyl, alkenyl, cycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl and optionally substitutedheterocyclic.
 28. The pharmaceutical composition according to claim 14,wherein R² is selected from the group consisting of: methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,—CH₂CH(CH₂CH₃)₂, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl,cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl,3-methylpentyl, —CH₂-cyclopropyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclohexyl, —CH₂-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-(HOOCCH₂O)—benzyl, 2-aminopyrid-6-yl,p-(N-morpholino-CH₂CH₂O)—benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol-4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thiophen-2-yl,—CH₂(1-methyl)cyclopropyl, —CH₂-thiophen-3-yl, thiophen-3-yl,thiophen-2-yl, —CH₂—C(O)O-t-butyl, —CH₂-C(CH₃)₃, —CH₂CH(CH₂CH₃)₂,2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH₃)₂]COOCH₃,—CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂, —CH₂CH═CHCH₃ (cis and trans), —CH₂OH,—CH(OH)CH₃, —CH(O-t-butyl)CH₃, —CH₂OCH₃, —(CH₂)₄NH—Boc, —(CH₂)₄NH₂,—CH₂-pyridyl, pyridyl, —CH₂-naphthyl, —CH₂-(N-morpholino),p-(N-morpholino-CH₂CH₂O)—benzyl, benzo[b]thiophen-2-yl,5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl,benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, —CH₂CH₂SCH₃, thien-2-yl,and thien-3-yl.
 29. A compound of formula IA:

R¹ is selected from the group consisting of: A) alkyl of from 1 to 20carbon atoms; B) alkenyl of from 2 to 10 carbon atoms and 1-2 sites ofalkenyl unsaturation; C) alkynyl of from 2 to 10 carbon atoms and from1-2 sites of alkynyl unsaturation; D) cycloalkyl of from 3 to 12 carbonatoms; E) cycloalkenyl of from 4 to 8 carbon atoms; F) substituted alkylof from 1 to 10 carbon atoms, having from 1 to 3 substituents selectedfrom: 1) alkoxy having the formula alkyl-O— wherein alkyl is as definedin A herein; 2) substituted alkoxy of the formula substituted alkyl-O—wherein substituted alkyl is as defined in F herein; 3) cycloalkyl asdefined in D herein; 4) substituted cycloalkyl as defined in I herein;5) cycloalkenyl as defined in E herein; 6) substituted cycloalkenyl asdefined in J herein; 7) acyl selected from alkyl-C(O)—, substitutedalkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, optionallysubstituted aryl-C(O)—, optionally substituted heteroaryl-C(O)— andoptionally substituted heterocyclic-C(O)— wherein alkyl is defined in Aherein; wherein substituted alkyl is defined in F herein; whereincycloalkyl is defined in D herein; wherein substituted cycloalkyl isdefined in I herein; wherein optionally substituted aryl is defined inF25 herein; wherein optionally substituted heteroaryl is defined in F27herein; and wherein optionally substituted heterocyclic is defined inF29 herein; 8) acylamino having the formula —C(O)NRR^(b) wherein each Ris independently hydrogen, alkyl, substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, or optionallysubstituted heterocyclic wherein alkyl is defined in A herein; whereinsubstituted alkyl is defined in F herein; wherein optionally substitutedaryl is defined in F25 herein; wherein optionally substituted heteroarylis defined in F27 herein; and wherein optionally substitutedheterocyclic is defined in F29 herein; 9) acyloxy selected fromalkyl-C(O)O—, substituted alkyl-C(O)O—, cycloalkyl-C(O)O—, optionallysubstituted aryl-C(O)O—, optionally substituted heteraryl-C(O)O— andoptionally substituted heterocyclic-C(O)O— wherein alkyl is defined in Aherein; wherein substituted alkyl is defined in F herein; whereincycloalkyl is defined in D herein; wherein optionally substituted arylis defined in F25 herein; wherein optionally substituted heteroaryl isdefined in F27 herein ; and wherein optionally substituted heterocyclicis defined in F29 herein; 10) amino; 11) substituted amino having theformula —N(R)₂ wherein each R is independently selected from the groupconsisting of: a) hydrogen; b) alkyl as defined in A herein; c)substituted alkyl as defined in F herein; d) alkenyl as defined in Bherein; e) substituted alkenyl as defined in G herein; f) alkynyl asdefined in C herein; g) substituted alkynyl as defined in H herein; h)optionally substituted aryl as defined in F25 herein; i) cycloalkyl asdefined in D herein; j) substituted cycloalkyl as defined in I herein;k) optionally substituted heteroaryl as defined in F27 herein; l)optionally substituted heterocyclic as defined in F29 herein and whereinone of R can also be hydrogen or R and R together with the nitrogen atomto which they are joined form an optionally substituted heterocyclic asdefined in F29 herein; 12) aminoacyl having the formula —NRC(O)R whereineach R is independently hydrogen, alkyl, substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, or optionallysubstituted heterocyclic wherein alkyl is defined in A herein; whereinsubstituted alkyl is defined in F herein; wherein optionally substitutedaryl is defined in F25 herein; wherein heteroaryl is defined in F27herein; and wherein optionally substituted heterocyclic is defined inF29 herein; 13) aminoacyloxy having the formula —NRC(O)OR wherein each Ris independently hydrogen, alkyl, substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, or optionallysubstituted heterocyclic wherein alkyl is defined in A herein; whereinsubstituted alkyl is defined in F herein; wherein optionally substitutedaryl is defined in F25 herein; wherein optionally substituted heteroarylis defined in F27 herein; and wherein optionally substitutedheterocyclic is defined in F29 herein; 14) oxyacylamino having theformula —OC(O)NRR wherein each R is independently hydrogen, alkyl,substituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, or optionally substituted heterocyclic wherein alkyl isdefined in A herein; wherein substituted alkyl is defined in F herein;wherein optionally substituted aryl is defined in F25 herein; whereinoptionally substituted heteroaryl is defined in F27 herein; and whereinoptionally substituted heterocyclic is defined in F29 herein; 15) cyano;16) halo selected from fluoro, chloro, bromo and iodo; 17) hydroxy; 18)carboxyl; 19) optionally substituted carboxyalkyl having the formula—C(O)O alkyl and —C(O)O substituted alkyl wherein alkyl is as defined inA and substituted alkyl is as defined in F; 20) keto; 21) thioketo; 22)thiol; 23) thioalkoxy having the formula —S-alkyl, wherein alkyl isdefined in A herein; 24) substituted thioalkoxy having the formula—S-substituted alkyl, wherein substituted alkyl is defined in F herein;25) optionally substituted aryl having 6 to 14 carbon atoms andoptionally substituted with 1 to 5 substituents selected from: a)acyloxy as defined in F9 herein; b) hydroxy; c) acyl as defined in F7herein; d) alkyl as defined in A herein; e) alkoxy as defined in F1herein; f) alkenyl as defined in B herein; g) alkynyl as defined in Cherein; h) substituted alkyl as defined in F herein; i) substitutedalkoxy as defined in F2 herein; j) substituted alkenyl as defined in Gherein; k) substituted alkynyl as defined in H herein; l) amino; m)substituted amino as defined in F11 herein; n) aminoacyl as defined inF12 herein; o) acylamino as defined in F8 herein; p) optionallysubstituted alkaryl in which the alkyl moiety has 1 to 8 carbon atomsand the aryl has 6 to 10 carbon atoms and is optionally substituted asdefined in F25 herein; q) optionally substituted aryl as defined in F25herein; r) optionally substituted aryloxy as defined in F26 herein; s)azido; t) carboxyl; u) optionally substituted carboxylalkyl as definedin F19 herein; v) cyano; w) halo as defined in F16 herein; x) nitro; y)optionally substituted heteroaryl as defined in F27 herein; z)optionally substituted heterocyclic as defined in F29 herein; aa)aminoacyloxy as defined in F13 herein; bb) oxyacylamino as defined inF14 herein; cc) thioalkoxy as defined in F23 herein; dd) substitutedthioalkoxy as defined in F24 herein; ee) optionally substitutedthioaryloxy having the formula aryl-S— wherein aryl is optionallysubstituted as defined in F25 herein; ff) optionally substitutedthioheteroaryloxy having the formula heteroaryl-S— wherein heteroaryl isoptionally substituted as defined in F27 herein; gg) —SO-alkyl whereinalkyl is as defined in A herein; hh) —SO-substituted alkyl whereinsubstituted alkyl is as defined in F herein; ii) —SO-optionallysubstituted aryl wherein optionally substituted aryl is as defined inF25 herein; jj) —SO— optionally substituted heteroaryl whereinoptionally substituted heteroaryl is as defined in F27 herein; kk)—SO₂-alkyl wherein alkyl is as defined in A herein; ll) —SO₂-substitutedalkyl wherein substituted alkyl is as defined in F herein; mm)—SO₂-optionally substituted aryl wherein optionally substituted aryl isas defined in F25 herein; nn) —SO₂-optionally substituted heteroarylwherein optionally substituted heteroaryl is as defined in F27 herein;and oo) trihalomethyl wherein halo is as defined in F16 herein; 26)optionally substituted aryloxy having the formula aryl-O— wherein arylis optionally substituted aryl as defined in F25 herein; 27) optionallysubstituted heteroaryl having 1 to 15 ring carbon atoms and 1 to 4 ringheteroatoms selected from oxygen, nitrogen and sulfur and optionallysubstituted with 1 to 5 substituents selected from the same group ofsubstituents as defined for optionally substituted aryl in F25 herein;28) optionally substituted heteroaryloxy having the formula—O-heteroaryl wherein heteroaryl is optionally substituted heteroaryl asdefined in F27 herein; 29) optionally substituted saturated orunsaturated heterocyclic from 1 to 15 ring carbon atoms and 1 to 4 ringheteroatoms selected from nitrogen, sulfur and oxygen and optionallysubstituted with 1 to 5 substituents selected from the same group ofsubstituents as defined for substituted alkyl in F herein; 30)optionally substituted heterocyclooxy having the formula —O-heterocyclicwherein heterocyclic is defined as optionally substituted heterocyclicon F29 hereof; 31) hydroxyamino; 32) alkoxyamino wherein alkoxy is asdefined in F1; 33) nitro; 34) —SO-alkyl wherein alkyl is as defined in Aherein; 35) —SO-substituted alkyl wherein substituted alkyl is asdefined in F herein; 36) —SO-optionally substituted aryl wherein aryl isoptionally substituted as defined in F25 herein; 37) —SO-optionallysubstituted heteroaryl wherein optionally substituted heteroaryl is asdefined in F27 herein; 38) —SO₂-alkyl wherein alkyl is as defined in Aherein; 39) —SO₂-substituted alkyl wherein substituted alkyl is asdefined in F herein; 40) —SO₂-optionally substituted aryl whereinoptionally substituted aryl is as defined in F25 herein; 41)—SO₂-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; G) substituted alkenyl having 2to 10 carbon atoms and having of from 1 to 3 substituents selected fromthe group consisting of: 1) alkoxy having the formula alkyl-O— whereinalkyl is as defined in A herein; 2) substituted alkoxy of the formulasubstituted alkyl-O— wherein substituted alkyl is as defined in Fherein; 3) cycloalkyl as defined in D herein; 4) substituted cycloalkylas defined in I herein; 5) cycloalkoxy; 6) substituted cycloalkoxy; 7)acyl as defined in F7 herein; 8) acylamino as defined in F8 herein; 9)acyloxy as defined in F9 herein; 10) amino; 11) substituted amino asdefined in F11 herein; 12) aminoacyl as defined in F12 herein; 13)aminoacycloxy as defined in F13 herein; 14) cyano; 15) halo selectedfrom fluoro, cholo, bromo and iodo; 16) hydroxy; 17) carboxyl; 18)optionally substituted carboxyalkyl having the formula —C(O)O-alkyl and—C(O)O-substituted alkyl wherein alkyl is as defined in A andsubstituted alkyl is as defined in F; 19) keto; 20) thioketo; 21) thiol;22) thioalkoxy as defined in F23 herein; 23) substituted thioalkoxy asdefined in F24 herein; 24) optionally substituted aryl as defined in F25herein; 25) optionally substituted heteroaryl as defined in F27 herein;26) optionally substituted saturated or unsaturated heterocyclic asdefined in F29 herein; 27) optionally substituted heterocyclooxy asdefined in G24 herein; 28) nitro; 29) —SO-alkyl wherein alkyl is asdefined in A herein; 30) —SO-substituted alkyl wherein substituted alkylis as defined in F herein; 31) —SO-aryl wherein optionally substitutedaryl is optionally substituted as defined in F25 herein; 32)—SO-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; 33) —SO₂-alkyl wherein alkyl isas defined in A herein; 34) —SO₂-substituted alkyl wherein substitutedalkyl is as defined in F herein; 35) —SO₂-optionally substituted arylwherein optionally substituted aryl is as defined in F25 herein; and 36)—SO₂-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; H) substituted alkynyl having 2to 10 carbon atoms having 1-2 sites of alkynyl unsaturation and having 1to 3 substituents selected from the same group of substituents asdefined for substituted alkenyl in G herein; I) substituted cycloalkylhaving 3 to 12 carbon atoms and having from 1 to 5 substituents selectedfrom the same group of substituents as defined for substituted alkyl inF herein; J) substituted cycloalkenyl as defined in E herein having from1 to 5 substituents selected from the same group of substituents asdefined for substituted alkyl in F herein; K) optionally substitutedaryl as defined in F25 herein; L) optionally substituted heteroaryl asdefined in F27 herein; and M) optionally substituted heterocyclic asdefined in F29 herein; a is an integer from 2 to 6; R^(2′) isindependently selected from the group consisting of: N) hydrogen; O)alkyl as defined in A herein; P) substituted alkyl as defined in Fherein; Q) alkenyl of from 2 to 10 carbon atoms and 1-2 sites of alkenylunsaturation; R) substituted alkenyl as defined in G herein; S) alkynylof from 2 to 10 carbon atoms and from 1-2 sites of alkynyl unsaturation;T) substituted alkynyl as defined in H herein; U) cycloalkyl of from 3to 12 carbon atoms; V) optionally substituted aryl as defined in F25herein; W) optionally substituted heteroaryl as defined in F27 herein;and X) optionally substituted heterocyclic as defined in F29 herein; Qis S and O;  wherein R¹⁵ is independently selected from the groupconsisting of: Y) hydrogen, Z) alkyl as defined in A herein; AA)substituted alkyl as defined in F herein; AB) optionally substitutedaryl as defined in F25 herein; AC) optionally substituted heterocyclicas defined in F29 herein; AD) optionally substituted heteroaryl asdefined in F27 herein;  wherein R^(15′) is independently selected fromthe group consisting of: AE) hydrogen, AF) hydroxyl, AG) alkyl asdefined in A herein; AH) substituted alkyl as defined in F herein; AI)optionally substituted aryl as defined in F25 herein; AJ) optionallysubstituted heterocyclic as defined in F29 herein; AK) optionallysubstituted heteroaryl as defined in F27 herein; and the moiety:

 is selected from the group having the formulas:

 wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene, and —N═CH—;each V is independently selected from the group consisting of hydroxy,acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino,substituted amino, aminoacyl, optionally substituted alkaryl, optionallysubstituted aryl, optionally substituted aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, optionally substituted heteroaryl,thioalkoxy, substituted thioalkoxy, and trihalomethyl; R^(b) is selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, acyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclic; R^(c) is selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclic, cycloalkyl, and substituted cycloalkyl; and tis an integer from 0 to 4; or pharmaceutically salts thereof; with thefollowing provisos: when R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ ishydrogen, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-onewhen R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ is hydrogen, then W,together with >CH and >C═O, does not form a2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-onewhen R¹-N(R^(15′))C(Q) is (2,5-dimethoxyphenyl)aminocarbonyl and R² ismethyl, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one and  when Q isS, R¹⁵ and R^(15′) are hydrogen, and the moiety:

 is selected from the group having the formulas:

 then R¹ is not phenyl.
 30. The compound according to claim 29, whereinthe moiety:

each V is independently selected from the group consisting of hydroxy,acyl as defined in F7, acyloxy as defined in F9, alkyl as defined in A,substituted alkyl as defined in F, alkoxy as defined in F1, substitutedalkoxy as defined in F2, alkenyl as defined in B, substituted alkenyl asdefined in G, alkynyl as defined in C, substituted alkynyl as defined inH, amino, substituted amino as defined in F11, aminoacyl as defined inF12, optionally substituted alkaryl as defined in F25, optionallysubstituted aryl as defined in F25, optionally substituted aryloxy asdefined in F26, carboxyl, carboxyalkyl, cyano, halo, nitro, optionallysubstituted heteroaryl as defined in F27, thioalkoxy, substitutedthioalkoxy as defined in F24, and trihalomethyl; and t is an integerfrom 0 to 4; R_(b) is selected from the group comprising hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl,heteroaryl, heterocyclic cycloalkyl, and substituted cycloalkyl; orpharmaceutically acceptable salts thereof.
 31. The compound according toclaim 29, wherein the moiety:

wherein R^(b) is selected from the group consisting of alkyl,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, alkynyl, acyl, optionally substituted aryl as defined inF25, optionally substituted heteroaryl as defined in F27, and optionallysubstituted heterocyclic as defined in F29; R^(c) is selected from thegroup consisting of alkyl as defined in A, substituted alkyl as definedin F, alkenyl, substituted alkenyl as defined in G, optionallysubstituted aryl as defined in F25, optionally substituted heteroaryl asdefined in F27, optionally substituted heterocyclic as defined in F29,cycloalkyl, and substituted cycloalkyl as defined in I; each V isindependently selected from the group consisting of hydroxy, acyl asdefined in F7, acyloxy as defined in F9, alkyl as defined in A,substituted alkyl as defined in F, alkoxy as defined in F1, substitutedalkoxy as defined in F2, alkenyl as defined in B, substituted alkenyl asdefined in G, alkynyl as defined in C, substituted alkynyl as defined inH, amino, substituted amino as defined in F11, aminoacyl as defined inF12, optionally substituted alkaryl as defined in F25, optionallysubstituted aryl as defined in F25, optionally substituted aryloxy asdefined in F26, carboxyl, carboxyalkyl, cyano, halo, nitro, optionallysubstituted heteroaryl as defined in F27, thioalkoxy, substitutedthioalkoxy as defined in F24, and trihalomethyl; and t is an integerfrom 0 to 4; or pharmaceutically acceptable salts thereof.
 32. Thecompound according to claim 29, wherein the moiety:

wherein R^(b) is selected from the group consisting of alkyl,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, alkynyl, acyl, optionally substituted aryl as defined inF25, optionally substituted heteroaryl as defined in F27, and optionallysubstituted heterocyclic as defined in F29; R^(c) is selected from thegroup consisting of alkyl as defined in A, substituted alkyl as definedin F, alkenyl, substituted alkenyl as defined in G, optionallysubstituted aryl as defined in F25, optionally substituted heteroaryl asdefined in F27, optionally substituted heterocyclic as defined in F29,cycloalkyl, and substituted cycloalkyl as defined in I; each V isindependently selected from the group consisting of hydroxy, acyl asdefined in F7, acyloxy as defined in F9, alkyl as defined in A,substituted alkyl as defined in F, alkoxy as defined in F1, substitutedalkoxy as defined in F2, alkenyl as defined in B, substituted alkenyl asdefined in G, alkynyl as defined in C, substituted alkynyl as defined inH, amino, substituted amino as defined in F11, aminoacyl as defined inF12, optionally substituted alkaryl as defined in F25, optionallysubstituted aryl as defined in F25, optionally substituted aryloxy asdefined in F26, carboxyl, carboxyalkyl, cyano, halo, nitro, optionallysubstituted heteroaryl as defined in F27, thioalkoxy, substitutedthioalkoxy as defined in F24, and trihalomethyl; and t is an integerfrom 0 to 4; w is an integer from 0 to 3; or pharmaceutically acceptablesalts thereof.
 33. The compound according to claim 29, wherein themoiety:

wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene and —N═CH—;R^(c) is selected from the group consisting of alkyl as defined in A,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, optionally substituted aryl as defined in F25, optionallysubstituted heteroaryl as defined in F27, optionally substitutedheterocyclic as defined in F29, cycloalkyl, and substituted cycloalkylas defined in I; each V is independently selected from the groupconsisting of hydroxy, acyl as defined in F7, acyloxy as defined in F9,alkyl as defined in A, substituted alkyl as defined in F, alkoxy asdefined in F1, substituted alkoxy as defined in F2, alkenyl as definedin B, substituted alkenyl as defined in G, alkynyl as defined in C,substituted alkynyl as defined in H, amino, substituted amino as definedin F11, aminoacyl as defined in F12, optionally substituted alkaryl asdefined in F25, optionally substituted aryl as defined in F25,optionally substituted aryloxy as defined in F26, carboxyl,carboxyalkyl, cyano, halo, nitro, optionally substituted heteroaryl asdefined in F27, thioalkoxy, substituted thioalkoxy as defined in F24,and trihalomethyl; and t is an integer from 0 to 4; w is an integer from0 to 3; or pharmaceutically acceptable salts thereof.
 34. The compoundaccording to claim 29, wherein the moiety:

R^(c) is selected from the group consisting of alkyl as defined in A,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, optionally substituted aryl as defined in F25, optionallysubstituted heteroaryl as defined in F27, optionally substitutedheterocyclic as defined in F29, cycloalkyl, and substituted cycloalkylas defined in I; each V is independently selected from the groupconsisting of hydroxy, acyl as defined in F7, acyloxy as defined in F9,alkyl as defined in A, substituted alkyl as defined in F, alkoxy asdefined in F1, substituted alkoxy as defined in F2, alkenyl as definedin B, substituted alkenyl as defined in G, alkynyl as defined in C,substituted alkynyl as defined in H, amino, substituted amino as definedin F11, aminoacyl as defined in F12, optionally substituted alkaryl asdefined in F25, optionally substituted aryl as defined in F25,optionally substituted aryloxy as defined in F26, carboxyl,carboxyalkyl, cyano, halo, nitro, optionally substituted heteroaryl asdefined in F27, thioalkoxy, substituted thioalkoxy as defined in F24,and trihalomethyl; and t is an integer from 0 to 4; w is an integer from0 to 3; or pharmaceutically acceptable salts thereof.
 35. The compoundaccording to claim 29, wherein R¹ is optionally substituted aryl oroptionally substituted heteroaryl.
 36. The compound according to claim29, wherein R¹ is selected from the group consisting of: (a) alkyl, (b)phenyl, (c) a substituted phenyl group of the formula:

 wherein R^(c) is selected fron the group consisting of acyl, alkyl,alkoxy, alkylalkoxy, azido, cyano, subsstituted amino, halo, hydrogen,nitro, trihalomethyl, thioalkoxy, and wherein R^(b) and R^(c) are fusedto form a heteroaryl or heterocyclic ring with the phenyl ring whereinthe heteroaryl or heterocyclic ring contains from 3 to 8 atoms of whichfrom 1 to 3 are heteroatoms independently selected from the groupconsisting of oxygen, nitrogen and sulfur, R^(b) and R^(b′) areindependently selected from the group consisting of hydrogen, halo,nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the provisothat when R^(c) is hydrogen, the R^(b) and R^(b′) are either bothhydrogen or both substituents other than hydrogen, (d) 2-naphthyl, (e)2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5substituents selected from the group consisting of alkyl, alkoxy, halo,cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl, (f)heteroaryl, and (g) substituted heteroaryl containing 1 to 3substituents selected from the group consisting of alkyl, alkoxy, aryl,aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxyprovided that said substituents are not othro to the heteroarylattachment to the —NH group.
 37. The compound according to claim 29,wherein R¹ is selected from the group consisting of mono-, di-, andtri-substituted phenyl groups.
 38. The compound according to claim 37,wherein R¹ is a monosubstituted phenyl selected from the groupconsisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl,4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl,4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.
 39. The compoundaccording to claim 37, wherein R¹ is a disubstituted phenyl selectedfrom the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl,3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl,3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.
 40. The compoundaccording to claim 37, wherein R¹ is a trisubstituted phenyl selectedfrom the group consisting of 3,4,5-trifluorophenyl and3,4,5-tricholorophenyl.
 41. The compound according to claim 29, whereinR¹ is selected from the group consisting of 2-naphthyl, quinolin-3-yl,2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl and phenyl.
 42. Thecompound according to claim 29, wherein R¹ is selected from the groupconsisting of: phenyl, 1-naphthyl, 2-naphthyl, n-butyl, 2-chlorophenyl,2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl,2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl,2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl,4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl,3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl,3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl,3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl,3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl,3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl,3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl,iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl,n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, —CH₂-cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl, pyrid-2-yl,pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl,thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl,benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl,thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl,3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl,1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl,(CH₃)₂CH═CHCH₂CH₂CH(CH₃)—, C(O)CH₂—, thien-2-yl-methyl,2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl,2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl,(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,(3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl,(4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl,(4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl,(4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl,(1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl,(4-methoxyphenyl)ethyl, CH₃OC(O)CH₂—, benzylthiomethyl,5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl,(2-methylbenzofuran-3-yl), methoxymethyl, CH₃CH═CH—, CH₃CH₂CH═CH—,(4-chlorophenyl)C(O)CH₂—, (4-fluorophenyl)C(O)CH₂—, (4-methoxyphenyl)C(O)CH₂—, 4-(fluorophenyl)—NHC(O)CH₂—, 1-phenyl-n-butyl,(phenyl)₂CHNHC(O)CH₂CH₂—, (CH₃)₂NC(O)CH₂—, (phenyl)₂CHNHC(O)CH₂CH₂—,methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH₂—,4-methoxyphenyl-C(O)CH₂—, phenyl-C(O)CH₂—, CH₃C(O)N(phenyl)-, ethenyl,methylthiomethyl, (CH₃)₃CNHC(O)CH₂—, 4-fluorophenyl-C(O)CH₂—,diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH₂—,benzo[b]thiophen-3-yl, (CH₃)₃COC(O)NHCH₂—, trans-styryl, H₂NC(O)CH₂CH₂—,2-trifluoromethylphenyl-C(O)CH₂, phenylC(O)NHCH(phenyl)CH₂—, mesityl,CH₃CH(═NHOH)CH₂—, 4—CH₃-phenyl-NHC(O)CH₂CH₂—, phenyl-C(O)CH(phenyl)CH₂—,(CH₃)₂CHC(O)NHCH(phenyl)-, CH₃CH₂OCH₂—, CH₃OC(O)CH(CH₃)(CH₂)₃—,2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2—CH₃-benzofuran-3-yl,2-(2,4-dichlorophenoxy)ethyl, SO₂CH₂—, 3-cyclohexyl-n-propyl,CF₃CH₂CH₂CH₂— and N-pyrrolidinyl.
 43. The compound according to claim29, wherein R² is selected from the group consisting of alkyl,substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl andheterocyclic.
 44. The compound according to claim 29, wherein R² isselected from the group consisting of methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH₂CH(CH₂CH₃)₂,2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl,cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl,—CH₂-cyclopropyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclohexyl, —CH₂-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,p-(N-morpholino-CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol-4-yl,—CH₂—(3-tetrahydrofuranyl), —CH₂-thiophen-2-yl,—CH₂(1-methyl)cyclopropyl, —CH₂-thiophen-3-yl, thiophen-3-yl,thiophen-2-yl, —CH₂—C(O)O-t-butyl, —CH₂—C(CH₃)₃, —CH₂CH(CH₂CH₃)₂,2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH₃)₂]COOCH₃,—CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂, —CH₂CH═CHCH₃ (cis and trans), —CH₂OH,—CH(OH)CH₃, —CH(O-t-butyl)CH₃, —CH₂OCH₃, —(CH₂)₄NH—Boc, —(CH₂)₄NH₂,—CH₂-pyridyl, pyridyl, —CH₂-naphthyl, —CH₂—(N-morpholino),p-(N-morpholino-CH₂CH₂O)-benzyl, benzo[b]thiophen-2-yl,5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl,benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, —CH₂CH₂SCH₃, thien-2-yl,and thien-3-yl.
 45. A method for inhibiting β-amyloid peptide releaseand/or its synthesis in a cell, which method comprises administering tosuch a cell an amount of a compound or a mixture of compounds effectivefor inhibiting the cellular release and/or synthesis of β-amyloidpeptide, wherein said compounds are represented by the following formulaIA:

R¹ is selected from the group consisting of: A) alkyl of from 1 to 20carbon atoms; B) alkenyl of from 2 to 10 carbon atoms and 1-2 sites ofalkenyl unsaturation; C) alkynyl of from 2 to 10 carbon atoms and from1-2 sites of alkynyl unsaturation; D) cycloalkyl of from 3 to 12 carbonatoms; E) cycloalkenyl of from 4 to 8 carbon atoms; F) substituted alkylof from 1 to 10 carbon atoms, having from 1 to 3 substituents selectedfrom: 1) alkoxy having the formula alkyl-O— wherein alkyl is as definedin A herein; 2) substituted alkoxy of the formula substituted alkyl-O—wherein substituted alkyl is as defined in F herein; 3) cycloalkyl asdefined in D herein; 4) substituted cycloalkyl as defined in I herein;5) cycloalkenyl as defined in E herein; 6) substituted cycloalkenyl asdefined in J herein; 7) acyl selected from alkyl-C(O)—, substitutedalkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, optionallysubstituted aryl-C(O)—, optionally substituted heteroaryl-C(O)— andoptionally substituted heterocyclic-C(O)— wherein alkyl is defined in Aherein; wherein substituted alkyl is defined in F herein; whereincycloalkyl is defined in D herein; wherein substituted cycloalkyl isdefined in I herein; wherein optionally substituted aryl is defined inF25 herein; wherein optionally substituted heteroaryl is defined in F27herein; and wherein optionally substituted heterocyclic is defined inF29 herein; 8) acylamino having the formula —C(O)NRR wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein optionally substituted heteroaryl isdefined in F27 herein; and wherein optionally substituted heterocyclicis defined in F29 herein; 9) acyloxy selected from alkyl-C(O)O—,substituted alkyl-C(O)O—, cycloalkyl-C(O)O—, optionally substitutedaryl-C(O)O—, optionally substituted heteraryl-C(O)O— and optionallysubstituted heterocyclic-C(O)O— wherein alkyl is defined in A herein;wherein substituted alkyl is defined in F herein; wherein cycloalkyl isdefined in D herein; wherein optionally substituted aryl is defined inF25 herein; wherein optionally substituted heteroaryl is defined in F27herein; and wherein optionally substituted heterocyclic is defined inF29 herein; 10) amino; 11) substituted amino having the formula —N(R)₂wherein each R is independently selected from the group consisting of:a) hydrogen; b) alkyl as defined in A herein; c) substituted alkyl asdefined in F herein; d) alkenyl as defined in B herein; e) substitutedalkenyl as defined in G herein; f) alkynyl as defined in C herein; g)substituted alkynyl as defined in H herein; h) optionally substitutedaryl as defined in F25 herein; i) cycloalkyl as defined in D herein; j)substituted cycloalkyl as defined in I herein; k) optionally substitutedheteroaryl as defined in F27 herein; l) optionally substitutedheterocyclic as defined in F29 herein and  wherein one of R can also behydrogen or R and R together with the nitrogen atom to which they arejoined form an optionally substituted heterocyclic as defined in F29herein; 12) aminoacyl having the formula —NRC(O)R wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein heteroaryl is defined in F27 herein; andwherein optionally substituted heterocyclic is defined in F29 herein;13) aminoacyloxy having the formula —NRC(O)OR wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein optionally substituted heteroaryl isdefined in F27 herein; and wherein optionally substituted heterocyclicis defined in F29 herein; 14) oxyacylamino having the formula —OC(O)NRRwherein each R is independently hydrogen, alkyl, substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted heterocyclic wherein alkyl is defined in Aherein; wherein substituted alkyl is defined in F herein; whereinoptionally substituted aryl is defined in F25 herein; wherein optionallysubstituted heteroaryl is defined in F27 herein; and wherein optionallysubstituted heterocyclic is defined in F29 herein; 15) cyano; 16) haloselected from fluoro, chloro, bromo and iodo; 17) hydroxy; 18) carboxyl;19) optionally substituted carboxyalkyl having the formula —C(O)O alkyland —C(O)O substituted alkyl wherein alkyl is as defined in A andsubstituted alkyl is as defined in F; 20) keto; 21) thioketo; 22) thiol;23) thioalkoxy having the formula —S-alkyl, wherein alkyl is defined inA herein; 24) substituted thioalkoxy having the formula —S-substitutedalkyl, wherein substituted alkyl is defined in F herein; 25) optionallysubstituted aryl having 6 to 14 carbon atoms and optionally substitutedwith 1 to 5 substituents selected from: a) acyloxy as defined in F9herein; b) hydroxy; c) acyl as defined in F7 herein; d) alkyl as definedin A herein; e) alkoxy as defined in F1 herein; f) alkenyl as defined inB herein; g) alkynyl as defined in C herein; h) substituted alkyl asdefined in F herein; i) substituted alkoxy as defined in F2 herein; j)substituted alkenyl as defined in G herein; k) substituted alkynyl asdefined in H herein; l) amino; m) substituted amino as defined in F11herein; n) aminoacyl as defined in F12 herein; o) acylamino as definedin F8 herein; p) optionally substituted alkaryl in which the alkylmoiety has 1 to 8 carbon atoms and the aryl has 6 to 10 carbon atoms andis optionally substituted as defined in F25 herein; q) optionallysubstituted aryl as defined in F25 herein; r) optionally substitutedaryloxy as defined in F26 herein; s) azido; t) carboxyl; u) optionallysubstituted carboxylalkyl as defined in F19 herein; v) cyano; w) halo asdefined in F16 herein; x) nitro; y) optionally substituted heteroaryl asdefined in F27 herein; z) optionally substituted heterocyclic as definedin F29 herein; aa) aminoacyloxy as defined in F13 herein; bb)oxyacylamino as defined in F14 herein; cc) thioalkoxy as defined in F23herein; dd) substituted thioalkoxy as defined in F24 herein; ee)optionally substituted thioaryloxy having the formula aryl-S— whereinaryl is optionally substituted as defined in F25 herein; ff) optionallysubstituted thioheteroaryloxy having the formula heteroaryl-S— whereinheteroaryl is optionally substituted as defined in F27 herein; gg)—SO-alkyl wherein alkyl is as defined in A herein; hh) —SO-substitutedalkyl wherein substituted alkyl is as defined in F herein; ii)—SO-optionally substituted aryl wherein optionally substituted aryl isas defined in F25 herein; jj) —SO— optionally substituted heteroarylwherein optionally substituted heteroaryl is as defined in F27 herein;kk) —SO₂— alkyl wherein alkyl is as defined in A herein; ll)—SO₂-substituted alkyl wherein substituted alkyl is as defined in Fherein; mm) —SO₂-optionally substituted aryl wherein optionallysubstituted aryl is as defined in F25 herein; nn) —SO₂-optionallysubstituted heteroaryl wherein optionally substituted heteroaryl is asdefined in F27 herein; and oo) trihalomethyl wherein halo is as definedin F16 herein; 26) optionally substituted aryloxy having the formulaaryl-O— wherein aryl is optionally substituted aryl as defined in F25herein; 27) optionally substituted heteroaryl having 1 to 15 ring carbonatoms and 1 to 4 ring heteroatoms selected from oxygen, nitrogen andsulfur and optionally substituted with 1 to 5 substituents selected fromthe same group of substituents as defined for optionally substitutedaryl in F25 herein; 28) optionally substituted heteroaryloxy having theformula —O-heteroaryl wherein heteroaryl is optionally substitutedheteroaryl as defined in F27 herein; 29) optionally substitutedsaturated or unsaturated heterocyclic from 1 to 15 ring carbon atoms and1 to 4 ring heteroatoms selected from nitrogen, sulfur and oxygen andoptionally substituted with 1 to 5 substituents selected from the samegroup of substituents as defined for substituted alkyl in F herein; 30)optionally substituted heterocyclooxy having the formula —O-heterocyclicwherein heterocyclic is defined as optionally substituted heterocyclicon F29 hereof; 31) hydroxyamino; 32) alkoxyamino wherein alkoxy is asdefined in F1; 33) nitro; 34) —SO-alkyl wherein alkyl is as defined in Aherein; 35) —SO-substituted alkyl wherein substituted alkyl is asdefined in F herein; 36) —SO-optionally substituted aryl wherein aryl isoptionally substituted as defined in F25 herein; 37) —SO-optionallysubstituted heteroaryl wherein optionally substituted heteroaryl is asdefined in F27 herein; 38) —SO₂-alkyl wherein alkyl is as defined in Aherein; 39) —SO₂-substituted alkyl wherein substituted alkyl is asdefined in F herein; 40) —SO₂-optionally substituted aryl whereinoptionally substituted aryl is as defined in F25 herein; 41)—SO₂-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; G) substituted alkenyl having 2to 10 carbon atoms and having of from 1 to 3 substituents selected fromthe group consisting of: 1) alkoxy having the formula alkyl-O— whereinalkyl is as defined in A herein; 2) substituted alkoxy of the formulasubstituted alkyl-O— wherein substituted alkyl is as defined in Fherein; 3) cycloalkyl as defined in D herein; 4) substituted cycloalkylas defined in I herein; 5) cycloalkoxy; 6) substituted cycloalkoxy; 7)acyl as defined in F7 herein; 8) acylamino as defined in F8 herein; 9)acyloxy as defined in F9 herein; 10) amino; 11) substituted amino asdefined in F11 herein; 12) aminoacyl as defined in F12 herein; 13)aminoacycloxy as defined in F13 herein; 14) cyano; 15) halo selectedfrom fluoro, cholo, bromo and iodo; 16) hydroxy; 17) carboxyl; 18)optionally substituted carboxyalkyl having the formula —C(O)O-alkyl and—C(O)O-substituted alkyl wherein alkyl is as defined in A andsubstituted alkyl is as defined in F; 19) keto; 20) thioketo; 21) thiol;22) thioalkoxy as defined in F23 herein; 23) substituted thioalkoxy asdefined in F24 herein; 24) optionally substituted aryl as defined in F25herein; 25) optionally substituted heteroaryl as defined in F27 herein;26) optionally substituted saturated or unsaturated heterocyclic asdefined in F29 herein; 27) optionally substituted heterocyclooxy asdefined in G24 herein; 28) nitro; 29) —SO-alkyl wherein alkyl is asdefined in A herein; 30) —SO-substituted alkyl wherein substituted alkylis as defined in F herein; 31) —SO-aryl wherein optionally substitutedaryl is optionally substituted as defined in F25 herein; 32)—SO-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; 33) —SO₂-alkyl wherein alkyl isas defined in A herein; 34) —SO₂-substituted alkyl wherein substitutedalkyl is as defined in F herein; 35) —SO₂-optionally substituted arylwherein optionally substituted aryl is as defined in F25 herein; and 36)—SO₂-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; H) substituted alkynyl having 2to 10 carbon atoms having 1-2 sites of alkynyl unsaturation and having 1to 3 substituents selected from the same group of substituents asdefined for substituted alkenyl in G herein; I) substituted cycloalkylhaving 3 to 12 carbon atoms and having from 1 to 5 substituents selectedfrom the same group of substituents as defined for substituted alkyl inF herein; J) substituted cycloalkenyl as defined in E herein having from1 to 5 substituents selected from the same group of substituents asdefined for substituted alkyl in F herein; K) optionally substitutedaryl as defined in F25 herein; L) optionally substituted heteroaryl asdefined in F27 herein; and M) optionally substituted heterocyclic asdefined in F29 herein; a is an integer from 2 to 6; R² is independentlyselected from the group consisting of: N) hydrogen; O) alkyl as definedin A herein; P) substituted alkyl as defined in F herein; Q) alkenyl offrom 2 to 10 carbon atoms and 1-2 sites of alkenyl unsaturation; R)substituted alkenyl as defined in G herein; S) alkynyl of from 2 to 10carbon atoms and from 1-2 sites of alkynyl unsaturation; T) substitutedalkynyl as defined in H herein; U) cycloalkyl of from 3 to 12 carbonatoms; V) optionally substituted aryl as defined in F25 herein; W)optionally substituted heteroaryl as defined in F27 herein; and X)optionally substituted heterocyclic as defined in F29 herein; Q is S andO;  wherein R¹⁵ is independently selected from the group consisting of:Y) hydrogen, Z) alkyl as defined in A herein; AA) substituted alkyl asdefined in F herein; AB) optionally substituted aryl as defined in F25herein; AC) optionally substituted heterocyclic as defined in F29herein; AD) optionally substituted heteroaryl as defined in F27 herein; wherein R¹⁵ is independently selected from the group consisting of: AE)hydrogen, AF) hydroxyl, AG) alkyl as defined in A herein; AH)substituted alkyl as defined in F herein; AI) optionally substitutedaryl as defined in F25 herein; AJ) optionally substituted heterocyclicas defined in F29 herein; AK) optionally substituted heteroaryl asdefined in F27 herein; and the moiety:

 is selected from the group having the formulas:

 wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene, and —N═CH—;each V is independently selected from the group consisting of hydroxy,acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino,substituted amino, aminoacyl, optionally substituted alkaryl, optionallysubstituted aryl, optionally substituted aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, optionally substituted heteroaryl,thioalkoxy, substituted thioalkoxy, and trihalomethyl; R^(b) is selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, acyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclic; R^(c) is selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclic, cycloalkyl, and substituted cycloalkyl; and tis an integer from 0 to 4; or pharmaceutically salts thereof; with thefollowing provisos: when R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ ishydrogen, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-onewhen R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ is hydrogen, then W,together with >CH and >C═O, does not form a2,3dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-oneand when R¹—N(R¹⁵′)C(Q) is (2,5-dimethoxyphenyl)aminocarbonyl and R² ismethyl, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.
 46. A methodfor inhibiting β-amyloid peptide release and/or its synthesis in amammalian subject thereby inhibiting onset of diseases mediated byβ-amyloid peptide which method comprises administering to said patient apharmaceutical composition comprising a pharmaceutically inert carrierand an effective amount of a compound or a mixture of compoundseffective for inhibiting the release and/or synthesis of β-amyloidpeptide, wherein said compounds are represented by the following formulaIA:

R¹ is selected from the group consisting of: A) alkyl of from 1 to 20carbon atoms; B) alkenyl of from 2 to 10 carbon atoms and 1-2 sites ofalkenyl unsaturation; C) alkynyl of from 2 to 10 carbon atoms and from1-2 sites of alkynyl unsaturation; D) cycloalkyl of from 3 to 12 carbonatoms; E) cycloalkenyl of from 4 to 8 carbon atoms; F) substituted alkylof from 1 to 10 carbon atoms, having from 1 to 3 substituents selectedfrom: 1) alkoxy having the formula alkyl-O— wherein alkyl is as definedin A herein; 2) substituted alkoxy of the formula substituted alkyl-O—wherein substituted alkyl is as defined in F herein; 3) cycloalkyl asdefined in D herein; 4) substituted cycloalkyl as defined in I herein;5) cycloalkenyl as defined in E herein; 6) substituted cycloalkenyl asdefined in J herein; 7) acyl selected from alkyl-C(O)—, substitutedalkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, optionallysubstituted aryl-C(O)—, optionally substituted heteroaryl-C(O)— andoptionally substituted heterocyclic-C(O)— wherein alkyl is defined in Aherein; wherein substituted alkyl is defined in F herein; whereincycloalkyl is defined in D herein; wherein substituted cycloalkyl isdefined in I herein; wherein optionally substituted aryl is defined inF25 herein; wherein optionally substituted heteroaryl is defined in F27herein; and wherein optionally substituted heterocyclic is defined inF29 herein; 8) acylamino having the formula —C(O)NRR wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein optionally substituted heteroaryl isdefined in F27 herein; and wherein optionally substituted heterocyclicis defined in F29 herein; 9) acyloxy selected from alkyl-C(O)O—,substituted alkyl-C(O)O—, cycloalkyl-C(O)O—, optionally substitutedaryl-C(O)O—, optionally substituted heteraryl-C(O)O— and optionallysubstituted heterocyclic-C(O)O— wherein alkyl is defined in A herein;wherein substituted alkyl is defined in F herein; wherein cycloalkyl isdefined in D herein; wherein optionally substituted aryl is defined inF25 herein; wherein optionally substituted heteroaryl is defined in F27herein; and wherein optionally substituted heterocyclic is defined inF29 herein; 10) amino; 11) substituted amino having the formula —N(R)₂wherein each R is independently selected from the group consisting of:a) hydrogen; b) alkyl as defined in A herein; c) substituted alkyl asdefined in F herein; d) alkenyl as defined in B herein; e) substitutedalkenyl as defined in G herein; f) alkynyl as defined in C herein; g)substituted alkynyl as defined in H herein; h) optionally substitutedaryl as defined in F25 herein; i) cycloalkyl as defined in D herein; j)substituted cycloalkyl as defined in I herein; k) optionally substitutedheteroaryl as defined in F27 herein; l) optionally substitutedheterocyclic as defined in F29 herein and  wherein one of R can also behydrogen or R and R together with the nitrogen atom to which they arejoined form an optionally substituted heterocyclic as defined in F29herein; 12) aminoacyl having the formula —NRC(O)R wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein heteroaryl is defined in F27 herein; andwherein optionally substituted heterocyclic is defined in F29 herein;13) aminoacyloxy having the formula —NRC(O)OR wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein optionally substituted heteroaryl isdefined in F27 herein; and wherein optionally substituted heterocyclicis defined in F29 herein; 14) oxyacylamino having the formula —OC(O)NRRwherein each R is independently hydrogen, alkyl, substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted heterocyclic wherein alkyl is defined in Aherein; wherein substituted alkyl is defined in F herein; whereinoptionally substituted aryl is defined in F25 herein; wherein optionallysubstituted heteroaryl is defined in F27 herein; and wherein optionallysubstituted heterocyclic is defined in F29 herein; 15) cyano; 16) haloselected from fluoro, chloro, bromo and iodo; 17) hydroxy; 18) carboxyl;19) optionally substituted carboxyalkyl having the formula —C(O)O alkyland —C(O)O substituted alkyl wherein alkyl is as defined in A andsubstituted alkyl is as defined in F; 20) keto; 21) thioketo; 22) thiol;23) thioalkoxy having the formula —S-alkyl, wherein alkyl is defined inA herein; 24) substituted thioalkoxy having the formula —S-substitutedalkyl, wherein substituted alkyl is defined in F herein; 25) optionallysubstituted aryl having 6 to 14 carbon atoms and optionally substitutedwith 1 to 5 substituents selected from: a) acyloxy as defined in F9herein; b) hydroxy; c) acyl as defined in F7 herein; d) alkyl as definedin A herein; e) alkoxy as defined in F1 herein; f) alkenyl as defined inB herein; g) alkynyl as defined in C herein; h) substituted alkyl asdefined in F herein; i) substituted alkoxy as defined in F2 herein; j)substituted alkenyl as defined in G herein; k) substituted alkynyl asdefined in H herein; l) amino; m) substituted amino as defined in F11herein; n) aminoacyl as defined in F12 herein; o) acylamino as definedin F8 herein; p) optionally substituted alkaryl in which the alkylmoiety has 1 to 8 carbon atoms and the aryl has 6 to 10 carbon atoms andis optionally substituted as defined in F25 herein; q) optionallysubstituted aryl as defined in F25 herein; r) optionally substitutedaryloxy as defined in F26 herein; s) azido; t) carboxyl; u) optionallysubstituted carboxylalkyl as defined in F19 herein; v) cyano; w) halo asdefined in F16 herein; x) nitro; y) optionally substituted heteroaryl asdefined in F27 herein; z) optionally substituted heterocyclic as definedin F29 herein; aa) aminoacyloxy as defined in F13 herein; bb)oxyacylamino as defined in F14 herein; cc) thioalkoxy as defined in F23herein; dd) substituted thioalkoxy as defined in F24 herein; ee)optionally substituted thioaryloxy having the formula aryl-S— whereinaryl is optionally substituted as defined in F25 herein; ff) optionallysubstituted thioheteroaryloxy having the formula heteroaryl-S— whereinheteroaryl is optionally substituted as defined in F27 herein; gg)—SO-alkyl wherein alkyl is as defined in A herein; hh) —SO-substitutedalkyl wherein substituted alkyl is as defined in F herein; ii)—SO-optionally substituted aryl wherein optionally substituted aryl isas defined in F25 herein; jj) —SO— optionally substituted heteroarylwherein optionally substituted heteroaryl is as defined in F27 herein;kk) —SO₂— alkyl wherein alkyl is as defined in A herein; ll) —SO₂—substituted alkyl wherein substituted alkyl is as defined in F herein;mm) —SO₂-optionally substituted aryl wherein optionally substituted arylis as defined in F25 herein; nn) —SO₂-optionally substituted heteroarylwherein optionally substituted heteroaryl is as defined in F27 herein;and oo) trihalomethyl wherein halo is as defined in F16 herein; 26)optionally substituted aryloxy having the formula aryl-O— wherein arylis optionally substituted aryl as defined in F25 herein; 27) optionallysubstituted heteroaryl having 1 to 15 ring carbon atoms and 1 to 4 ringheteroatoms selected from oxygen, nitrogen and sulfur and optionallysubstituted with 1 to 5 substituents selected from the same group ofsubstituents as defined for optionally substituted aryl in F25 herein;28) optionally substituted heteroaryloxy having the formula—O-heteroaryl wherein heteroaryl is optionally substituted heteroaryl asdefined in F27 herein; 29) optionally substituted saturated orunsaturated heterocyclic from 1 to 15 ring carbon atoms and 1 to 4 ringheteroatoms selected from nitrogen, sulfur and oxygen and optionallysubstituted with 1 to 5 substituents selected from the same group ofsubstituents as defined for substituted alkyl in F herein; 30)optionally substituted heterocyclooxy having the formula —O-heterocyclicwherein heterocyclic is defined as optionally substituted heterocyclicon F29 hereof; 31) hydroxyamino; 32) alkoxyamino wherein alkoxy is asdefined in F1; 33) nitro; 34) —SO-alkyl wherein alkyl is as defined in Aherein; 35) —SO-substituted alkyl wherein substituted alkyl is asdefined in F herein; 36) —SO-optionally substituted aryl wherein aryl isoptionally substituted as defined in F25 herein; 37) —SO-optionallysubstituted heteroaryl wherein optionally substituted heteroaryl is asdefined in F27 herein; 38) —SO₂-alkyl wherein alkyl is as defined in Aherein; 39) —SO₂-substituted alkyl wherein substituted alkyl is asdefined in F herein; 40) —SO₂-optionally substituted aryl whereinoptionally substituted aryl is as defined in F25 herein; 41)—SO₂-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; G) substituted alkenyl having 2to 10 carbon atoms and having of from 1 to 3 substituents selected fromthe group consisting of: 1) alkoxy having the formula alkyl-O— whereinalkyl is asdefined in A herein; 2) substituted alkoxy of the formulasubstituted alkyl-O— wherein substituted alkyl is as defined in Fherein; 3) cycloalkyl as defined in D herein; 4) substituted cycloalkylas defined in I herein; 5) cycloalkoxy; 6) substituted cycloalkoxy; 7)acyl as defined in F7 herein; 8) acylamino as defined in F8 herein; 9)acyloxy as defined in F9 herein; 10) amino; 11) substituted amino asdefined in F11 herein; 12) aminoacyl as defined in F12 herein; 13)aminoacycloxy as defined in F13 herein; 14) cyano; 15) halo selectedfrom fluoro, cholo, bromo and iodo; 16) hydroxy; 17) carboxyl; 18)optionally substituted carboxyalkyl having the formula —C(O)O-alkyl and—C(O)O-substituted alkyl wherein alkyl is as defined in A andsubstituted alkyl is as defined in F; 19) keto; 20) thioketo; 21) thiol;22) thioalkoxy as defined in F23 herein; 23) substituted thioalkoxy asdefined in F24 herein; 24) optionally substituted aryl as defined in F25herein; 25) optionally substituted heteroaryl as defined in F27 herein;26) optionally substituted saturated or unsaturated heterocyclic asdefined in F29 herein; 27) optionally substituted heterocyclooxy asdefined in G24 herein; 28) nitro; 29) —SO-alkyl wherein alkyl is asdefined in A herein; 30) —SO-substituted alkyl wherein substituted alkylis as defined in F herein; 31) —SO-aryl wherein optionally substitutedaryl is optionally substituted as defined in F25 herein; 32)—SO-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; 33) —SO₂-alkyl wherein alkyl isas defined in A herein; —SO₂-substituted alkyl wherein substituted alkylis as defined in F herein; 35) —SO₂-optionally substituted aryl whereinoptionally substituted aryl is as defined in F25 herein; and 36)—SO₂-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; H) substituted alkynyl having 2to 10 carbon atoms having 1-2 sites of alkynyl unsaturation and having 1to 3 substituents selected from the same group of substituents asdefined for substituted alkenyl in G herein; I) substituted cycloalkylhaving 3 to 12 carbon atoms and having from 1 to 5 substituents selectedfrom the same group of substituents as defined for substituted alkyl inF herein; J) substituted cycloalkenyl as defined in E herein having from1 to 5 substituents selected from the same group of substituents asdefined for substituted alkyl in F herein; K) optionally substitutedaryl as defined in F25 herein; L) optionally substituted heteroaryl asdefined in F27 herein; and M) optionally substituted heterocyclic asdefined in F29 herein; a is an integer from 2 to 6; R^(2′) isindependently selected from the group consisting of: N) hydrogen; O)alkyl as defined in A herein; P) substituted alkyl as defined in Fherein; Q) alkenyl of from 2 to 10 carbon atoms and 1-2 sites of alkenylunsaturation; R) substituted alkenyl as defined in G herein; S) alkynylof from 2 to 10 carbon atoms and from 1-2 sites of alkynyl unsaturation;T) substituted alkynyl as defined in H herein; U) cycloalkyl of from 3to 12 carbon atoms; V) optionally substituted aryl as defined in F25herein; W) optionally substituted heteroaryl as defined in F27 herein;and X) optionally substituted heterocyclic as defined in F29 herein; Qis S and O;  wherein R¹⁵ is independently selected from the groupconsisting of: Y) hydrogen, Z) alkyl as defined in A herein; AA)substituted alkyl as defined in F herein; AB) optionally substitutedaryl as defined in F25 herein; AC) optionally substituted heterocyclicas defined in F29 herein; AD) optionally substituted heteroaryl asdefined in F27 herein; wherein R^(15′) is independently selected fromthe group consisting of: AE) hydrogen; AF) hydroxyl; AG) alkyl asdefined in A herein; AH) substituted alkyl as defined in F herein; AI)optionally substituted aryl as defined in F25 herein; AJ) optionallysubstituted heterocyclic as defined in F29 herein; AK) optionallysubstituted heteroaryl as defined in F27 herein; and the moiety:

 is selected from the group having the formulas:

 wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene, and —N═CH—;each V is independently selected from the group consisting of hydroxy,acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino,substituted amino, aminoacyl, optionally substituted alkaryl, optionallysubstituted aryl, optionally substituted aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, optionally substituted heteroaryl,thioalkoxy, substituted thioalkoxy, and trihalomethyl; R^(b) is selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, acyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclic; R^(c) is selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclic, cycloalkyl, and substituted cycloalkyl; and tis an integer from 0 to 4; or pharmaceutically salts thereof; with thefollowing provisos: when R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ ishydrogen, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-onewhen R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ is hydrogen, then W,together with >CH and >C═O, does not form a2,3dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-oneand when R¹—N(R¹⁵′)C(Q) is (2,5-dimethoxyphenyl)aminocarbonyl and R² ismethyl, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.
 47. A methodfor treating a human patient with AD in order to inhibit furtherdeterioration in the condition of that patient, which method comprisesadministering to said patient a pharmaceutical composition comprising apharmaceutically inert carrier and a compound or a mixture of compoundsin an amount effective for inhibiting further deterioration in thecondition of said patient, wherein said compounds are represented by thefollowing formula IA:

R¹ is selected from the group consisting of: A) alkyl of from 1 to 20carbon atoms; B) alkenyl of from 2 to 10 carbon atoms and 1-2 sites ofalkenyl unsaturation; C) alkynyl of from 2 to 10 carbon atoms and from1-2 sites of alkynyl unsaturation; D) cycloalkyl of from 3 to 12 carbonatoms; E) cycloalkenyl of from 4 to 8 carbon atoms; F) substituted alkylof from 1 to 10 carbon atoms, having from 1 to 3 substituents selectedfrom: 1) alkoxy having the formula alkyl-O— wherein alkyl is as definedin A herein; 2) substituted alkoxy of the formula substituted alkyl-O—wherein substituted alkyl is as defined in F herein; 3) cycloalkyl asdefined in D herein; 4) substituted cycloalkyl as defined in I herein;5) cycloalkenyl as defined in E herein; 6) substituted cycloalkenyl asdefined in J herein; 7) acyl selected from alkyl-C(O)—, substitutedalkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, optionallysubstituted aryl-C(O)—, optionally substituted heteroaryl-C(O)— andoptionally substituted heterocyclic-C(O)— wherein alkyl is defined in Aherein; wherein substituted alkyl is defined in F herein; whereincycloalkyl is defined in D herein; wherein substituted cycloalkyl isdefined in I herein; wherein optionally substituted aryl is defined inF25 herein; wherein optionally substituted heteroaryl is defined in F27herein; and wherein optionally substituted heterocyclic is defined inF29 herein; 8) acylamino having the formula —C(O)NRR wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein optionally substituted heteroaryl isdefined in F27 herein; and wherein optionally substituted heterocyclicis defined in F29 herein; 9) acyloxy selected from alkyl-C(O)O—,substituted alkyl-C(O)—, cycloalkyl-C(O)O—, optionally substitutedaryl-C(O)O—, optionally substituted heteraryl-C(O)O— and optionallysubstituted heterocyclic-C(O)O— wherein alkyl is defined in A herein;wherein substituted alkyl is defined in F herein; wherein cycloalkyl isdefined in D herein; wherein optionally substituted aryl is defined inF25 herein; wherein optionally substituted heteroaryl is defined in F27herein; and wherein optionally substituted heterocyclic is defined inF29 herein; 10) amino; 11) substituted amino having the formula —N(R)₂wherein each R is independently selected from the group consisting of:a) hydrogen; b) alkyl as defined in A herein; c) substituted alkyl asdefined in F herein; d) alkenyl as defined in B herein; e) substitutedalkenyl as defined in G herein; f) alkynyl as defined in C herein; g)substituted alkynyl as defined in H herein; h) optionally substitutedaryl as defined in F25 herein; i) cycloalkyl as defined in D herein; j)substituted cycloalkyl as defined in I herein; k) optionally substitutedheteroaryl as defined in F27 herein; l) optionally substitutedheterocyclic as defined in F29 herein and wherein one of R can also behydrogen or R and R together with the nitrogen atom to which they arejoined form an optionally substituted heterocyclic as defined in F29herein; 12) aminoacyl having the formula —NRC(O)R wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein heteroaryl is defined in F27 herein; andwherein optionally substituted heterocyclic is defined in F29 herein;13) aminoacyloxy having the formula —NRC(O)OR wherein each R isindependently hydrogen, alkyl, substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclic wherein alkyl is defined in A herein; wherein substitutedalkyl is defined in F herein; wherein optionally substituted aryl isdefined in F25 herein; wherein optionally substituted heteroaryl isdefined in F27 herein; and wherein optionally substituted heterocyclicis defined in F29 herein; 14) oxyacylamino having the formula —OC(O)NRRwherein each R is independently hydrogen, alkyl, substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted heterocyclic wherein alkyl is defined in Aherein; wherein substituted alkyl is defined in F herein; whereinoptionally substituted aryl is defined in F25 herein; wherein optionallysubstituted heteroaryl is defined in F27 herein; and wherein optionallysubstituted heterocyclic is defined in F29 herein; 15) cyano; 16) haloselected from fluoro, chloro, bromo and iodo; 17) hydroxy; 18) carboxyl;19) optionally substituted carboxyalkyl having the formula C(O)O alkyland —C(O)O substituted alkyl wherein alkyl is as defined in A andsubstituted alkyl is as defined in F; 20) keto; 21) thioketo; 22) thiol;23) thioalkoxy having the formula —S-alkyl, wherein alkyl is defined inA herein; 24) substituted thioalkoxy having the formula —S-substitutedalkyl, wherein substituted alkyl is defined in F herein; 25) optionallysubstituted aryl having 6 to 14 carbon atoms and optionally substitutedwith 1 to 5 substituents selected from: a) acyloxy as defined in F9herein; b) hydroxy; c) acyl as defined in F7 herein; d) alkyl as definedin A herein; e) alkoxy as defined in F1 herein; f) alkenyl as defined inB herein; g) alkynyl as defined in C herein; h) substituted alkyl asdefined in F herein; i) substituted alkoxy as defined in F2 herein; j)substituted alkenyl as defined in G herein; k) substituted alkynyl asdefined in H herein; l) amino; m) substituted amino as defined in F11herein; n) aminoacyl as defined in F12 herein; o) acylamino as definedin F8 herein; p) optionally substituted alkaryl in which the alkylmoiety has 1 to 8 carbon atoms and the aryl has 6 to 10 carbon atoms andis optionally substituted as defined in F25 herein; q) optionallysubstituted aryl as defined in F25 herein; r) optionally substitutedaryloxy as defined in F26 herein; s) azido; t) carboxyl; u) optionallysubstituted carboxylalkyl as defined in F19 herein; v) cyano; w) halo asdefined in F16 herein; x) nitro; y) optionally substituted heteroaryl asdefined in F27 herein; z) optionally substituted heterocyclic as definedin F29 herein; aa) aminoacyloxy as defined in F13 herein; bb)oxyacylamino as defined in F14 herein; cc) thioalkoxy as defined in F23herein; dd) substituted thioalkoxy as defined in F24 herein; ee)optionally substituted thioaryloxy having the formula aryl-S— whereinaryl is optionally substituted as defined in F25 herein; ff) optionallysubstituted thioheteroaryloxy having the formula heteroaryl-S— whereinheteroaryl is optionally substituted as defined in F27 herein; gg)—SO-alkyl wherein alkyl is as defined in A herein; hh) —SO-substitutedalkyl wherein substituted alkyl is as defined in F herein; ii)—SO-optionally substituted aryl wherein optionally substituted aryl isas defined in F25 herein; jj) —SO— optionally substituted heteroarylwherein optionally substituted heteroaryl is as defined in F27 herein;kk) —SO₂— alkyl wherein alkyl is as defined in A herein; ll) —SO₂—substituted alkyl wherein substituted alkyl is as defined in F herein;mm) —SO₂-optionally substituted aryl wherein optionally substituted arylis as defined in F25 herein; nn) —SO₂-optionally substituted heteroarylwherein optionally substituted heteroaryl is as defined in F27 herein;and oo) trihalomethyl wherein halo is as defined in F16 herein; 26)optionally substituted aryloxy having the formula aryl-O— wherein arylis optionally substituted aryl as defined in F25 herein; 27) optionallysubstituted heteroaryl having 1 to 15 ring carbon atoms and 1 to 4 ringheteroatoms selected from oxygen, nitrogen and sulfur and optionallysubstituted with 1 to 5 substituents selected from the same group ofsubstituents as defined for optionally substituted aryl in F25 herein;28) optionally substituted heteroaryloxy having the formula—O-heteroaryl wherein heteroaryl is optionally substituted heteroaryl asdefined in F27 herein; 29) optionally substituted saturated orunsaturated heterocyclic from 1 to 15 ring carbon atoms and 1 to 4 ringheteroatoms selected from nitrogen, sulfur and oxygen and optionallysubstituted with 1 to 5 substituents selected from the same group ofsubstituents as defined for substituted alkyl in F herein; 30)optionally substituted heterocyclooxy having the formula —O-heterocyclicwherein heterocyclic is defined as optionally substituted heterocyclicon F29 hereof; 31) hydroxyamino; 32) alkoxyamino wherein alkoxy is asdefined in F1; 33) nitro; 34) —SO-alkyl wherein alkyl is as defined in Aherein; 35) —SO-substituted alkyl wherein substituted alkyl is asdefined in F herein; 36) —SO-optionally substituted aryl wherein aryl isoptionally substituted as defined in F25 herein; 37) —SO-optionallysubstituted heteroaryl wherein optionally substituted heteroaryl is asdefined in F27 herein; 38) —SO₂-alkyl wherein alkyl is as defined in Aherein; 39) —SO₂-substituted alkyl wherein substituted alkyl is asdefined in F herein; 40) —SO₂-optionally substituted aryl whereinoptionally substituted aryl is as defined in F25 herein; 41)—SO₂-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; G) substituted alkenyl having 2to 10 carbon atoms and having of from 1 to 3 substituents selected fromthe group consisting of: 1) alkoxy having the formula alkyl-O— whereinalkyl is as defined in A herein; 2) substituted alkoxy of the formulasubstituted alkyl-O— wherein substituted alkyl is as defined in Fherein; 3) cycloalkyl as defined in D herein; 4) substituted cycloalkylas defined in I herein; 5) cycloalkoxy; 6) substituted cycloalkoxy; 7)acyl as defined in F7 herein; 8) acylamino as defined in F8 herein; 9)acyloxy as defined in F9 herein; 10) amino; 11) substituted amino asdefined in F11 herein; 12) aminoacyl as defined in F12 herein; 13)aminoacycloxy as defined in F13 herein; 14) cyano; 15) halo selectedfrom fluoro, cholo, bromo and iodo; 16) hydroxy; 17) carboxyl; 18)optionally substituted carboxyalkyl having the formula —C(O)O-alkyl and—C(O)O-substituted alkyl wherein alkyl is as defined in A andsubstituted alkyl is as defined in F; 19) keto; 20) thioketo; 21) thiol;22) thioalkoxy as defined in F23 herein; 23) substituted thioalkoxy asdefined in F24 herein; 24) optionally substituted aryl as defined in F25herein; 25) optionally substituted heteroaryl as defined in F27 herein;26) optionally substituted saturated or unsaturated heterocyclic asdefined in F29 herein; 27) optionally substituted heterocyclooxy asdefined in G24 herein; 28) nitro; 29) —SO-alkyl wherein alkyl is asdefined in A herein; 30) —SO-substituted alkyl wherein substituted alkylis as defined in F herein; 31) —SO-aryl wherein optionally substitutedaryl is optionally substituted as defined in F25 herein; 32)—SO-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; 33) —SO₂-alkyl wherein alkyl isas defined in A herein; 34) —SO₂-substituted alkyl wherein substitutedalkyl is as defined in F herein; 35) —SO₂-optionally substituted arylwherein optionally substituted aryl is as defined in F25 herein; and 36)—SO₂-optionally substituted heteroaryl wherein optionally substitutedheteroaryl is as defined in F27 herein; H) substituted alkynyl having 2to 10 carbon atoms having 1-2 sites of alkynyl unsaturation and having 1to 3 substituents selected from the same group of substituents asdefined for substituted alkenyl in G herein; I) substituted cycloalkylhaving 3 to 12 carbon atoms and having from 1 to 5 substituents selectedfrom the same group of substituents as defined for substituted alkyl inF herein; J) substituted cycloalkenyl as defined in E herein having from1 to 5 substituents selected from the same group of substituents asdefined for substituted alkyl in F herein; K) optionally substitutedaryl as defined in F25 herein; L) optionally substituted heteroaryl asdefined in F27 herein; and M) optionally substituted heterocyclic asdefined in F29 herein; a is an integer from 2 to 6; R² is independentlyselected from the group consisting of: N) hydrogen; O) alkyl as definedin A herein; P) substituted alkyl as defined in F herein; Q) alkenyl offrom 2 to 10 carbon atoms and 1-2 sites of alkenyl unsaturation; R)substituted alkenyl as defined in G herein; S) alkynyl of from 2 to 10carbon atoms and from 1-2 sites of alkynyl unsaturation; T) substitutedalkynyl as defined in H herein; U) cycloalkyl of from 3 to 12 carbonatoms; V) optionally substituted aryl as defined in F25 herein; W)optionally substituted heteroaryl as defined in F27 herein; and X)optionally substituted heterocyclic as defined in F29 herein; Q is S andO;  wherein R¹⁵ is independently selected from the group consisting of:Y) hydrogen; Z) alkyl as defined in A herein; AA) substituted alkyl asdefined in F herein; AB) optionally substituted aryl as defined in F25herein; AC) optionally substituted heterocyclic as defined in F29herein; AD) optionally substituted heteroaryl as defined in F27 herein; wherein R^(15′) is independently selected from the group consisting of:AE) hydrogen; AF) hydroxyl; AG) alkyl as defined in A herein; AH)substituted alkyl as defined in F herein; AI) optionally substitutedaryl as defined in F25 herein; AJ) optionally substituted heterocyclicas defined in F29 herein; AK) optionally substituted heteroaryl asdefined in F27 herein; and the moiety:

 is selected from the group having the formulas:

 wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene, and —N═CH—;each V is independently selected from the group consisting of hydroxy,acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino,substituted amino, aminoacyl, optionally substituted alkaryl, optionallysubstituted aryl, optionally substituted aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, optionally substituted heteroaryl,thioalkoxy, substituted thioalkoxy, and trihalomethyl; R^(b) is selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, acyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclic; R^(c) is selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclic, cycloalkyl, and substituted cycloalkyl; and tis an integer from 0 to 4; or pharmaceutically salts thereof; with thefollowing provisos: when R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ ishydrogen, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-onewhen R¹ is trans-cinnamyl, R² is methyl, and R¹⁵ is hydrogen, then W,together with >CH and >C═O, does not form a2,3dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-oneand when R¹—N(R¹⁵′)C(Q) is (2,5-dimethoxyphenyl)aminocarbonyl and R² ismethyl, then W, together with >CH and >C═O, does not form a2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.
 48. The methodaccording to claims 45, 46, 47, wherein the moiety:

each V is independently selected from the group consisting of hydroxy,acyl as defined in F7, acyloxy as defined in F9, alkyl as defined in A,substituted alkyl as defined in F, alkoxy as defined in F1, substitutedalkoxy as defined in F2, alkenyl as defined in B, substituted alkenyl asdefined in G, alkynyl as defined in C, substituted alkynyl as defined inH, amino, substituted amino as defined in F11, aminoacyl as defined inF12, optionally substituted alkaryl as defined in F25, optionallysubstituted aryl as defined in F25, optionally substituted aryloxy asdefined in F26, carboxyl, carboxyalkyl, cyano, halo, nitro, optionallysubstituted heteroaryl as defined in F27, thioalkoxy, substitutedthioalkoxy as defined in F24, and trihalomethyl; and t is an integerfrom 0 to 4; R_(b) is selected from the group comprising hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl,heteroaryl, heterocyclic cycloalkyl, and substituted cycloalkyl; orpharmaceutically acceptable salts thereof.
 49. The method according toclaims 45, 46 or 47, wherein the moiety:

wherein R^(b) is selected from the group consisting of alkyl,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, alkynyl, acyl, optionally substituted aryl as defined inF25, optionally substituted heteroaryl as defined in F27, and optionallysubstituted heterocyclic as defined in F29; R^(c) is selected from thegroup consisting of alkyl as defined in A, substituted alkyl as definedin F, alkenyl, substituted alkenyl as defined in G, optionallysubstituted aryl as defined in F25, optionally substituted heteroaryl asdefined in F27, optionally substituted heterocyclic as defined in F29,cycloalkyl, and substituted cycloalkyl as defined in I; each V isindependently selected from the group consisting of hydroxy, acyl asdefined in F7, acyloxy as defined in F9, alkyl as defined in A,substituted alkyl as defined in F, alkoxy as defined in F1, substitutedalkoxy as defined in F2, alkenyl as defined in B, substituted alkenyl asdefined in G, alkynyl as defined in C, substituted alkynyl as defined inH, amino, substituted amino as defined in F11, aminoacyl as defined inF12, optionally substituted alkaryl as defined in F25, optionallysubstituted aryl as defined in F25, optionally substituted aryloxy asdefined in F26, carboxyl, carboxyalkyl, cyano, halo, nitro, optionallysubstituted heteroaryl as defined in F27, thioalkoxy, substitutedthioalkoxy as defined in F24, and trihalomethyl; and t is an integerfrom 0 to 4; or pharmaceutically acceptable salts thereof.
 50. Themethod according to claims 45, 46 or 47, wherein the moiety:

wherein R^(b) is selected from the group consisting of alkyl,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, alkynyl, acyl, optionally substituted aryl as defined inF25, optionally substituted heteroaryl as defined in F27, and optionallysubstituted heterocyclic as defined in F29; R^(c) is selected from thegroup consisting of alkyl as defined in A, substituted alkyl as definedin F, alkenyl, substituted alkenyl as defined in G, optionallysubstituted aryl as defined in F25, optionally substituted heteroaryl asdefined in F27, optionally substituted heterocyclic as defined in F29,cycloalkyl, and substituted cycloalkyl as defined in I; each V isindependently selected from the group consisting of hydroxy, acyl asdefined in F7, acyloxy as defined in F9, alkyl as defined in A,substituted alkyl as defined in F, alkoxy as defined in F1, substitutedalkoxy as defined in F2, alkenyl as defined in B, substituted alkenyl asdefined in G, alkynyl as defined in C, substituted alkynyl as defined inH, amino, substituted amino as defined in F12, aminoacyl as defined inF12, optionally substituted alkaryl as defined in F25, optionallysubstituted aryl as defined in F25, optionally substituted aryloxy asdefined in F26, carboxyl, carboxyalkyl, cyano, halo, nitro, optionallysubstituted heteroaryl as defined in F27, thioalkoxy, substitutedthioalkoxy as defined in F24, and trihalomethyl; and t is an integerfrom 0 to 4; w is an integer from 0 to 3; or pharmaceutically acceptablesalts thereof.
 51. The method according to claims 45, 46 or 47, whereinthe moiety:

wherein A—B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene and —N═CH—;R^(c) is selected from the group consisting of alkyl as defined in A,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, optionally substituted aryl as defined in F25, optionallysubstituted heteroaryl as defined in F27, optionally substitutedheterocyclic as defined in F29, cycloalkyl, and substituted cycloalkylas defined in I; each V is independently selected from the groupconsisting of hydroxy, acyl as defined in F7, acyloxy as defined in F9,alkyl as defined in A, substituted alkyl as defined in F, alkoxy asdefined in F1, substituted alkoxy as defined in F2, alkenyl as definedin B, substituted alkenyl as defined in G, alkynyl as defined in C,substituted alkynyl as defined in H, amino, substituted amino as definedin F11, aminoacyl as defined in F12, optionally substituted alkaryl asdefined in F25, optionally substituted aryl as defined in F25,optionally substituted aryloxy as defined in F26, carboxyl,carboxyalkyl, cyano, halo, nitro, optionally substituted heteroaryl asdefined in F27, thioalkoxy, substituted thioalkoxy as defined in F24,and trihalomethyl; and t is an integer from 0 to 4; w is an integer from0 to 3; or pharmaceutically acceptable salts thereof.
 52. The methodaccording to claims 45, 46 or 47, wherein the moiety:

R^(c) is selected from the group consisting of alkyl as defined in A,substituted alkyl as defined in F, alkenyl, substituted alkenyl asdefined in G, optionally substituted aryl as defined in F25, optionallysubstituted heteroaryl as defined in F27, optionally substitutedheterocyclic as defined in F29, cycloalkyl, and substituted cycloalkylas defined in I; each V is independently selected from the groupconsisting of hydroxy, acyl as defined in F7, acyloxy as defined in F9,alkyl as defined in A, substituted alkyl as defined in F, alkoxy asdefined in F1, substituted alkoxy as defined in F2, alkenyl as definedin B, substituted alkenyl as defined in G, alkynyl as defined in C,substituted alkynyl as defined in H, amino, substituted amino as definedin F11, aminoacyl as defined in F12, optionally substituted alkaryl asdefined in F25, optionally substituted aryl as defined in F25,optionally substituted aryloxy as defined in F26, carboxyl,carboxyalkyl, cyano, halo, nitro, optionally substituted heteroaryl asdefined in F27, thioalkoxy, substituted thioalkoxy as defined in F24,and trihalomethyl; and t is an integer from 0 to 4; w is an integer from0 to 3; or pharmaceutically acceptable salts thereof.
 53. The methodaccording to claims 45, 46 or 47, wherein R¹ is optionally substitutedaryl or optionally substituted heteroaryl.
 54. The method according toclaims 45, 46 or 47, wherein R¹ is selected from the group consistingof: (a) alkyl; (b) phenyl; (c) a substituted phenyl group of theformula:

 wherein R^(c) is selected from the group consisting of acyl, alkyl,alkoxy, alkylalkoxy, azido, cyano, substituted amino, halo, hydrogen,nitro, trihalomethyl, thioalkoxy, and wherein R^(b) and R^(c) are fusedto form a heteroaryl or heterocyclic ring with the phenyl ring whereinthe heteroaryl or heterocyclic ring contains from 3 to 8 atoms of whichfrom 1 to 3 are heteroatoms independently selected from the groupconsisting of oxygen, nitrogen and sulfur, R^(b) and R^(b′) areindependently selected from the group consisting of hydrogen, halo,nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the provisothat when R^(c) is hydrogen, the R^(b) and R^(b′) are either bothhydrogen or both substituents other than hydrogen, (d) 2-naphthyl, (e)2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5substituents selected from the group consisting of alkyl, alkoxy, halo,cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl, (f)heteroaryl, and (g) substituted heteroaryl containing 1 to 3substituents selected from the group consisting of alkyl, alkoxy, aryl,aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxyprovided that said substituents are not othro to the heteroarylattachment to the —NH group.
 55. The method according to claims 45, 46or 47, wherein R¹ is selected from the group consisting of mono-, di-,and tri-substituted phenyl groups.
 56. The method according to claim 55,wherein R¹ is a monosubstituted phenyl selected from the groupconsisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl,4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl,4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.
 57. The methodaccording to claim 55, wherein R¹ is a disubstituted phenyl selectedfrom the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl,3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3-(trifluoromethyl)-4-chlorophenyl, 3-chloro4-cyanophenyl,3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.
 58. The methodaccording to claim 55, wherein R¹ is a trisubstituted phenyl selectedfrom the group consisting of 3,4,5-trifluorophenyl and3,4,5-tricholorophenyl.
 59. The method according to claim 58, wherein R¹is selected from the group consisting of 2-naphthyl, quinolin-3-yl,2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl and phenyl.
 60. Themethod according to claim 45, 46 or 47, wherein R¹ is selected from thegroup consisting of: phenyl, 1-naphthyl, 2-naphthyl, 2-chlorophenyl,2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl,2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl,2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl,4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl,3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl,3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl,3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl,3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl,3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl,3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl,iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl,n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, —CH₂-cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl, pyrid-2-yl,pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl,thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl,benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl,thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl,3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl,1-phenyl-tetrazol-5-yl, allyl, 2-(cyclohexyl)ethyl,(CH₃)₂CH═CHCH₂CH₂CH(CH₃)—, C(O)CH₂—, thien-2-yl-methyl,2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl,2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl,(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,(3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl,(4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl,(4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl,(4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl,(1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl,(4-methoxyphenyl)ethyl, CH₃OC(O)CH₂—, benzylthiomethyl,5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl,(2-methylbenzofuran-3-yl), methoxymethyl, CH₃CH═CH—, CH₃CH₂CH═CH—,(4-chlorophenyl)C(O)CH₂—, (4-fluorophenyl)C(O)CH₂—,(4-methoxyphenyl)C(O)CH₂—, 4-(fluorophenyl)—NHC(O)CH₂—,1-phenyl-n-butyl, (phenyl)₂CHNHC(O)CH₂CH₂—, (CH₃)₂NC(O)CH₂—,(phenyl)₂CHNHC(O)CH₂CH₂—, ethylcarbonylmethyl,(2,4-dimethylphenyl)C(O)CH₂—, 4-methoxyphenyl-C(O)CH₂—, phenyl-C(O)CH₂—,CH₃C(O)N(phenyl)-, ethenyl, methylthiomethyl, (CH₃)₃CNHC(O)CH₂—,4-fluorophenyl-C(O)CH₂—, diphenylmethyl, phenoxymethyl,3,4-methylenedioxyphenyl-CH₂—, benzo[b]thiophen-3-yl,(CH₃)₃COC(O)NHCH₂—, trans-styryl, H₂NC(O)CH₂CH₂—,2-trifluoromethylphenyl-C(O)CH₂, phenyl-C(O)NHCH(phenyl)CH₂—, mesityl,CH₃CH(═NHOH)CH₂—, 4—CH₃-phenyl-NHC(O)CH₂CH₂—, C(O)CH(phenyl)CH₂—,(CH₃)₂CHC(O)NHCH(phenyl)-, CH₃CH₂OCH₂—, CH₃OC(O)CH(CH₃)(CH₂)₃—,2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2—CH₃-benzofuran-3-yl,2-(2,4-dichlorophenoxy)ethyl, SO₂CH₂—, 3-cyclohexyl-n-propyl,CF₃CH₂CH₂CH₂— and N-pyrrolidinyl.
 61. The method according to claim 45,46 or 47, wherein R² is selected from the group consisting of alkyl,substituted alkyl, alkenyl, cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl and optionally substitutedheterocyclic.
 62. The method according to claim 45, 46 or 47, wherein R²is selected from the group consisting of: methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH₂CH(CH₂CH₃)₂,2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl,cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl,—CH₂-cyclopropyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclohexyl, —CH₂-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,p-(N-morpholino-CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol-4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thiophen-2-yl,—CH₂(1-methyl)cyclopropyl, —CH₂-thiophen-3-yl, thiophen-3-yl,thiophen-2-yl, —CH₂—C(O)O-t-butyl, —CH₂—C(CH₃)₃, —CH₂CH(CH₂CH₃)₂,2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH₃)₂]COOCH₃,—CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂, —CH₂CH═CHCH₃ (cis and trans), —CH₂OH,—CH(OH)CH₃, —CH(O-t-butyl)CH₃, —CH₂OCH₃, —(CH₂)₄NH—Boc, —(CH₂)₄NH₂,—CH₂-pyridyl, pyridyl, —CH₂-naphthyl, —CH₂-(N-morpholino),p-(N-morpholino-CH₂CH₂O)-benzyl, benzo[b]thiophen-2-yl,5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl,benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, —CH₂CH₂SCH₃, thien-2-yl,and thien-3-yl.
 63. A compound selected from the group consisting of:(S)-3-[(N′-(trans-2-phenylcyclopropyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-3,4-dichlorophenyl)aminocarbonyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-H-1,4-benzodaizepin-2-one(S)-3-[(N′-((2-propenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((R)-(−)-1-(1-naphthyl)ethyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3[(N′-((2,6-diisopropylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((3-[(trifluoromethyl)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-ethoxycarbonylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-bromophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-one(S)-3-[(N′-((o-tolyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((ethyl-6-methylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((fluorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2,4-difluorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-ethoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((3-acetylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[N′-((3-[(cyano)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((phenethyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-n-butylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((octyl)aminocarbonyl)-L-alaninyl)]amino-2,3dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-biphenyl)aminocarbonyl)-L-alaninyl)]amino2,3-hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-isopropylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one(S)-3-[(N′-((hexyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-isopropylphenyl)aminocarbonyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-,4-benzodiazepin-2-one(S)-3-[(N′-((2,6-difluorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H1,4-1,4-benzodiazepin-2-one(S)-3-[(N′-((octadecyl)aminocarbonyl-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,1,4-benzodiazepin-2-one(S)-3-[(N′-((4-(trifluoromethoxy)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one(S)-3-[(N′-((2,4-dichlorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((ethoxycarbonylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-chlorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-4,4-benzodiazepin-2-one(S)-3-[(N′-((4-butoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-phenoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((1-naphthyl)aminocarbonyl)-L-alaninyl)]amino2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-biphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H11,4-benzodiazepin-2-one(S)-3-[(N′-((2-(methylthio)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-ethyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-(methoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-(trimethoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-(trimethoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-methyl-6-t-butylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-(thiophenyl)ethyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-oneand3-[(N′-3,5-difluorophenyl-acetamido)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.64. A pharmaceutical composition comprising a pharmaceutically inertcarrier and a pharmaceutically effective amount of a compound selectedfrom the group consisting of:(S)-3-[(N′-(trans-2-phenylcyclopropyl)aminocarbonyl)-Lalaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-3,4-dichlorophenyl)aminocarbonyl)-Lalaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-H-1,4-benzodaizepin-2-one(S)-3-[(N′-((2-propenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((R)-(−)-1-(1-naphthyl)ethyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3[(N′-((2,6-diisopropylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((3-[(trifluoromethyl)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-ethoxycarbonylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-bromophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-one(S)-3-[(N′-((o-tolyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((ethyl-6-methylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((fluorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2,4-difluorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-ethoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((3-acetylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[N′-((3-[(cyano)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((phenethyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-n-butylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((octyl)aminocarbonyl)-L-alaninyl)]amino-2,3dihydro-1-methyl-5-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-biphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-isopropylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one(S)-3-[(N′-((hexyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-isopropylphenyl)aminocarbonyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1-,4-benzodiazepin-2-one(S)-3-[(N′-((2,6-difluorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H1,4-1,4-benzodiazepin-2-one(S)-3-[(N′-((octadecyl)aminocarbonyl-L-alaninyl)]amino2,3-dihydro-1-methyl-5-phenyl-1H-1,1,4-benzodiazepin-2-one(S)-3-[(N′-((4-(trifluoromethoxy)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one(S)-3-[(N′-((2,4-dichlorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((ethoxycarbonylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-chlorophenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-4,4-benzodiazepin-2-one(S)-3-[(N′-((4-butoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((4-phenoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((1-naphthyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-biphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H11,4-benzodiazepin-2-one(S)-3-[(N′-((2-(methylthio)phenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-ethyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-(methoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-(trimethoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-(trimethoxyphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-methyl-6-t-butylphenyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-[(N′-((2-(thiophenyl)ethyl)aminocarbonyl)-L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-oneand3-[(N′-3,5-difluorophenyl-acetamido)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.65. A method for inhibiting β-amyloid peptide release and/or itssynthesis in a cell, which method comprises administering to such a cellan amount of a compound according to claim 63, or a mixture of compoundseffective for inhibiting the cellular release and/or synthesis ofβ-amyloid peptide.
 66. A method for inhibiting β-amyloid peptide releaseand/or its synthesis in a mammalian subject thereby inhibiting onset ofdiseases mediated by β-amyloid peptide which method comprisesadministering to said patient a pharmaceutical composition according toclaim 64 in an amount effective for inhibiting the release and/orsynthesis of β-amyloid peptide.
 67. A method for treating a humanpatient with AD in order to inhibit further deterioration in thecondition of that patient, which method comprises administering to saidpatient a pharmaceutical composition according to claim 64 in an amounteffective for inhibiting further deterioration in the condition of saidpatient.
 68. The compound according to claim 29, wherein each R¹⁵ is H.69. The compound according to claim 42, wherein each R² is independentlyselected from the group consisting of alkyl, susbstituted alkyl,alkenyl, cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl and optionally substituted heterocyclic.
 70. The compoundaccording to claim 69, wherein each R² is independently selected fromthe group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, —CH₂CH(CH₂CH₃)₂, 2-methyl-n-butyl,6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl,allyl, iso-but-2-enyl, 3-methylpentyl, —CH₂-cyclopropyl,—CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclohexyl,—CH₂-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl,p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl,m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,p-(N-morpholino-CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol-4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thiophen-2-yl,—CH₂(1-methyl)cyclopropyl, —CH₂-thiophen-3-yl, thiophen-3-yl,thiophen-2-yl, —CH₂—C(O)O-t-butyl, —CH₂—C(CH₃)₃, —CH₂CH(CH₂CH₃)₂,2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH₃)₂]COOCH₃,—CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂, —CH₂CH═CHCH₃ (cis and trans), —CH₂OH,—CH(OH)CH₃, —CH(O-t-butyl)CH₃, —CH₂OCH₃, —(CH₂)₄NH—Boc, —(CH₂)₄NH₂,—CH₂-pyridyl, pyridyl, —CH₂-naphthyl, —CH₂—(N-morpholino),p-(N-morpholino-CH₂CH₂O)-benzyl, benzo[b]thiophen-2-yl,5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl,benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, —CH₂CH₂SCH₃, thien-2-yl,and thien-3-yl.
 71. The compound according to claim 70, wherein R^(b) isselected from the group consisting of alkyl, substituted alkyl,cycloalkyl and aryl.
 72. The compound according to claim 71, wherein R²is methyl.
 73. The compound according to claim 72, wherein R¹ is alkyl.74. The compound according to claim 73, wherein R^(b) is alkyl.
 75. Thecompound according to claim 36, wherein R¹ is selected from the groupconsisting of methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl,n-butyl and n-pentyl.
 76. The pharmaceutical composition according toclaim 14, wherein R¹ is optionally substituted aryl or optionallysubstituted heteroaryl.